Cyclic compounds, their production and use

ABSTRACT

Novel compounds of the following general formula or salts thereof. ##STR1## wherein Ring M is a heterocyclic ring having --N═CC&lt;, --CO--N&lt; or --CS--N&lt; as the partial structure --X . . . . . Y&lt;; R a  and R b  are bonded to each other to form Ring A, or they are the same or different and represent, independently, a hydrogen atom or a substituent on the Ring M; Ring A and Ring B represent, independently, an optionally substituted homocyclic or heterocyclic ring, and at least one of them is optionally substituted heterocyclic ring; Ring C is optionally substituted homocyclic or heterocyclic ring; Ring Z is an optionally substituted ring; and n represents an integer of from 1 to 6, or a salt thereof, which has an excellent tachykinin receptor antagonistic effect, and their production, and pharmaceutical compositions.

This application is a divisional of application Ser. No. 08/621,360,filed Mar. 25, 1996 now U.S. Pat. No. 5,786,352.

The present invention relates to novel cyclic compounds having anexcellent tachykinin receptor antagonistic effect, and a method forproducing them, as well as a composition containing the foregoing cycliccompounds.

Capsaicine is a stimulative essential component to be in a capsicum, andthis is known as a substance which selectively stimulates C-fiberscomprising substance P (hereinafter simply referred to as SP),neurokinin A (NKA), calcitonin gene-related peptides (CGRP), etc. of theprimary sensory nerve to thereby liberate such intrinsic neuropeptides.

Tachykinin is a generic term for a group of neuropeptides. Substance P(SP) , neurokinin A (NKA) and neurokinin B (NKB) are known in mammals,and it is known that these peptides bind to the corresponding receptors(neurokinin-1, neurokinin-2, neurokinin-3) that exist in living body tothereby exhibit various biological activities.

Of such neuropeptides, substance P has the longest history and has beenstudied in detail. In 1931, the existence of substance P in the extractfrom equine intestines was confirmed, and its structure was determinedin 1971. Substance P is a peptide consisting of 11 amino acids. It isknown that substance P plays an important role in the peripheral andcentral nervous systems as an information transmitter substance or thelike. In addition, it is considered that substance P participates invarious disorders (for example, pain, inflammation, allergy,pollakisuria, urinary incontinence, respiratory tract disorders,psycosis, etc.)

Substance P is broadly distributed over the central and peripheralnervous systems, while having, in addition to the function as atransmitter substance for primary sensory neurons, various physiologicalactivities for vasodilation, promotion of vascular extravasation,contraction of smooth muscles, neuronal excitatory activity, salivation,promotion of diuresis, immunological enhancement, etc. In particular, itis known that SP liberated from the terminal of the spinal (dorsal) horndue to a pain impulse transmits the pain to secondary neurons and thatSP liberated from the peripheral terminal induces an inflammatoryresponse in the nociceptive field. In addition, it is considered that SPis involved in Alzheimer type dementia [see review article:Physiological Reviews, Vol. 73, pp. 229-308, (1993); Journal ofAutonomic Pharmacology, Vol. 13, pp. 23-93, (1993)].

At present, the following compounds have been known as those having asubstance P receptor antagonistic effect.

(1) In Japanese Patent Laid-Open No. 1-287095, disclosed are compoundsof a formula:

    R.sup.1 -A-D-Trp(R.sup.2)-Phe--R.sup.3

wherein R¹ represents a hydrogen atom or an amino-protecting group; R²represents a hydrogen atom, an amino-protecting group, acarbamoyl-(lower) alkyl group, a carboxy-(lower) alkyl group, or aprotected carboxy-(lower) alkyl group; R³ represents an ar-(lower) alkylgroup, a group of a formula: ##STR2## wherein R⁴ and R⁵ represent,independently, a hydrogen atom, an aryl group or an optionallysubstituted lower alkyl group, or R⁴ and R⁵ are bonded to each other toform a benzene-condensed lower alkylene group, or a group of a formula:

    --OR.sup.6

wherein

R⁶ represents a hydrogen atom, an aryl group or an optionallysubstituted lower alkyl group;

A represents a single bond or one or two amino acid residues, providedthat when A is one amino acid residue of -D-Trp-, R⁴ is not be ahydrogen atom, and a salt thereof.

(2) In EP-A-436,334, disclosed are compounds of a formula: ##STR3## etc.

(3) In EP-A-429,366, disclosed are compounds of a formula: ##STR4## etc.

(4) In Journal of Medicinal Chemistry, Vol. 34, p. 1751 (1991),disclosed are compounds of a formula: ##STR5## etc.

(5) In WO91/09844, disclosed are compounds of a formula: ##STR6## etc.

(6) In EP-A-522,808, disclosed are compounds of a formula: ##STR7## etc.

(7) In WO93/01169, disclosed are compounds of a formula: ##STR8## etc.

(8) In EP-A-532,456, disclosed are compounds of a formula: ##STR9## etc.

(9) In Bioorganic & Medicinal Chemistry Letters, Vol. 4, p. 1903 (1994),disclosed is a compound of a formula: ##STR10##

(10) In European Journal of Pharmacology, Vol. 250, p. 403 (1993),disclosed is a compound of a formula: ##STR11##

(11) In EP-A-585,913, disclosed are compounds of a formula: ##STR12##wherein Ring A may be optionally substituted;

Ring B represents an optionally substituted benzene ring;

one of X and Y represents --NR¹ -- (where R¹ represents a hydrogen atom,an optionally substituted hydrocarbon group, an optionally substitutedhydroxyl group or an optionally substituted amino group), --O-- or--S--, while the other represents --CO--, --CS-- or --C(R²)R^(2a) --(where R² and R^(2a) represent, independently, a hydrogen atom or anoptionally substituted hydrocarbon group); or one of these represents--N═C, while the other represents ═CR³ -- (where R³ represents ahydrogen atom, a halogen atom, an optionally substituted hydrocarbongroup, an optionally substituted amino group, a substituted hydroxylgroup, or a mercapto group optionally substituted by an optionallysubstituted hydrocarbon group);

. . . . represents a single bond or a double bond;

Z represents ═CR⁴ -- (where R⁴ represents a hydrogen atom, a hydroxylgroup or an optionally substituted hydrocarbon group) or a nitrogenatom, when . . . . . adjacent to Z is a single bond, and represents acarbon atom when . . . . . adjacent to Z is a double bond;

D represents a C₁₋₃ alkylene group optionally substituted by oxo orthioxo group(s), or D and Y may together form a 5- to 7-membered ringoptionally substituted by oxo or thioxo group(s);

E represents --NR⁵ -- (where R⁵ represents a hydrogen atom, or anoptionally substituted hydrocarbon group, or R⁵ and Y may together forma 5- to 7-membered ring optionally substituted by oxo or thioxogroup(s)), --O-- or --S(O)_(n) -- (where n represents 0, 1 or 2);

G represents a bond or a C₁₋₃ alkylene group;

Ar represents an optionally substituted aryl group or an optionallysubstituted heterocyclic group;

provided that (i) when --X--Y-- is --O--CO-- or --CO--O--, D is --CO--and E is --NR⁵ --, then (a) G is a C₁₋₃ alkylene group, and Ar is asubstituted aryl group or a substituted heterocyclic group, or (b) G isa bond, and R⁵ is an optionally substituted hydrocarbon group, and (ii)when --X--Y-- is --NH--CO--, then D is --CO--, or a salt thereof, etc.

On the other hand, the following compounds have been known as thosehaving a neurokinin-A receptor antagonistic effect.

(1) In Life Sciences, Vol. 50, PL101 (1992), disclosed are compounds ofa formula: ##STR13## etc.

(2) In Bioorganic & Medicinal Chemistry Letters, Vol. 4, P.1951 (1994),disclosed are compounds of a formula: ##STR14## etc.

(3) In AFMC International Medicinal Chemistry Symposium (Tokyo), P6M139(1995.9), disclosed are compounds of a formula: ##STR15## etc.

(4) In Tachykinins (Florence), P.21 (1995.10), disclosed are compoundsof a formula: ##STR16## etc.

(5) In Journal of Medicinal Chemistry, Vol. 38, P.3772 (1995), disclosedare compounds of a formula: ##STR17## etc.

(6) In Bioorganic & Medicinal Chemistry Letters, Vol. 5, P.2879 (1995),disclosed are compounds of a formula: ##STR18## etc.

However, these references do not disclose condensed heterocycliccompounds having a basic skeleton of a formula: ##STR19## wherein Ring Mis a heterocyclic ring having --N═C<, --CO--N< or --CS--N< as thepartial structure --X . . . . . Y<;

R^(a) and R^(b) are bonded to each other to form Ring A, or they are thesame or different and represent, independently, a hydrogen atom or asubstituent on the Ring M;

Ring A and Ring B represent, independently, an optionally substitutedhomocyclic or heterocyclic ring, and at least one of them is anoptionally substituted heterocyclic ring; and

Ring Z is an optionally substituted nitrogen-containing heterocyclicring. Nor do these references disclose the properties of such compounds.

At present, compounds which have excellent tachykinin receptorantagonistic effects (especially, substance P and NKA receptorantagonistic effects) and are sufficiently satisfactory as medicines forthe above-mentioned various disorders (especially, pollakisuria, urinaryincontinence, etc.) from the viewpoint of the safety of themselves andthe persistency of their effects have not been found as of yet.Therefore, it is desired to develop compounds which have chemicalstructures different from those of the above-mentioned known compoundsand which have an excellent tachykinin receptor antagonistic effect andare therefore sufficiently satisfactory as medicines for such disorders.

Accordingly, the object of the present invention is to provide novelcompounds having high tachykinin receptor antagonistic effects(especially, substance P and NKA receptor antagonistic effects) and amethod for producing them, etc.

The other object of the present invention is to provide pharmaceuticalcompositions having a high tachykinin receptor antagonistic effects(especially, a substance P and NKA receptor antagonistic effects),tachykinin receptor antagonists and ameliorative preparations fordisorders of micturition, etc.

The present inventors have assiduously studied in consideration of theabove-mentioned situation and, as a result, have synthesized for thefirst time condensed heterocyclic compounds having, as the basicskeleton, a partial chemical structure of a formula: ##STR20## whereinthe symbols have the same meanings as mentioned above, and have foundunexpectedly that these condensed heterocyclic compounds have excellenttachykinin receptor antagonistic effects (especially, substance P andNKA receptor antagonistic effects) as based on their peculiar chemicalstructures and are sufficiently satisfactory as medicines. On the basisof these findings, the present inventors have completed the presentinvention.

Specifically, the present invention relates to

(1) A compound of the formula (I): ##STR21## wherein ring M is aheterocyclic ring having --N═C<, --CO--N< or --CS--N< as the partialstructure --X . . . . . Y<;

R^(a) and R.sup. b are bonded to each other to form Ring A, or they arethe same or different and represent, independently, a hydrogen atom or asubstituent on the Ring M;

Ring A and Ring B represent, independently, an optionally substitutedhomocyclic or heterocyclic ring, and at least one of them is anoptionally substituted heterocyclic ring;

Ring C is an optionally substituted homocyclic or heterocyclic ring;

Ring Z is an optionally substituted nitrogen-containing heterocyclicring; and

n is an integer of 1 to 6, or a salt thereof,

(2) A compound as described in (1), wherein

R^(a) and R^(b) are the same or different and represent, independently,

(i) a hydrogen atom,

(ii) a C₁₋₆ alkyl group optionally having from 1 to 5 substituentsselected from

(a) a hydroxyl group,

(b) a C₁₋₆ alkoxy group,

(c) a C₁₋₆ alkylthio group,

(d) an amino group,

(e) a C₁₋₇ acylamino group,

(f) a carboxyl group,

(g) a nitro group,

(h) a mono- or di-C₁₋₆ alkylamino group,

(i) a mono- or di-C₃₋₈ cycloalkylamino group,

(j) a C₆₋₁₀ arylamino group,

(h) a 5-membered to 9-membered cyclicamino group which may have 1 to 3hetero atoms selected from nitrogen, oxygen and sulfur atoms,

(l) a 5-membered to 6-membered aromatic heterocyclic group having from 1to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, inaddition to carbon atoms,

(m) a 5-membered to 9-membered non-aromatic heterocyclic ring havingfrom 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfuratoms, in addition to carbon atoms,

(n) a C₁₋₄ alkylsulfonylamino group,

(o) a C₁₋₆ alkyl-carbonyloxy group and

(p) a halogen atom,

(iii) an optionally halogenated C₁₋₆ alkoxy group,

(iv) an optionally halogenated C₁₋₆ alkylthio group,

(v) a C₃₋₁₀ cycloalkyl group,

(vi) a C₆₋₁₀ aryl group,

(vii) a C₁₋₇ acylamino group,

(viii) a C₁₋₃ acyloxy group,

(ix) a hydroxy group,

(x) a nitro group,

(xi) a cyano group,

(xii) an amino group,

(xiii) a mono- or di-C₁₋₆ alkylamino group,

(xiv) a 5-membered to 9-membered cyclicamino group which may have 1 to 3hetero atoms selected from nitrogen, oxygen and sulfur atoms, inaddition to one nitrogen atom,

(xv) a C₁₋₆ alkylcarbonylamino group,

(xvi) a C₁₋₆ alkylsulfonylamino group,

(xvii) a C₁₋₆ alkoxycarbonyl group,

(xviii) a carboxyl group,

(xix) a C₁₋₆ alkylcarbonyl group,

(xx) a carbamoyl group,

(xxi) a mono- or di-C₁₋₆ alkylcarbamoyl group,

(xxii) C₁₋₆ alkylsulfonyl group, or

(xxiii) an oxo group; or

R^(a) and R^(b) are bonded to each other to form Ring A, and the Ring Ais a 5-membered to 6-membered aromatic group having from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms, in addition tocarbon atoms, a 5-membered to 9-membered non-aromatic heterocyclic grouphaving from 1 to 3 hetero atoms selected from nitrogen, oxygen andsulfur atoms, in addition to carbon atoms, or a 3-membered to10-membered cyclic hydrocarbon group each of which may have 1 to 4substituents selected from

(i) a halogen atom,

(ii) a C₁₋₆ alkyl group optionally having from 1 to 5 substituentsselected from

(a) a hydroxyl group,

(b) an amino group,

(c) a carboxyl group,

(d) a nitro group,

(e) a mono- or di-C₁₋₆ alkylamino group,

(f) a C₁₋₆ alkyl-carbonyloxy group and

(g) a halogen atom,

(iii) an optionally halogenated C₁₋₆ alkoxy group,

(iv) an optionally halogenated C₁₋₆ alkylthio group,

(v) a C₆₋₁₀ aryl group,

(vi) a C₁₋₇ acylamino group,

(vii) a C₁₋₃ acyloxy group,

(viii) a hydroxy group,

(ix) a nitro group,

(x) a cyano group,

(xi) an amino group,

(xii) a mono- or di-C₁₋₆ alkylamino group,

(xiii) a 5-membered to 9-membered cyclicamino group which may have 1 to3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, inaddition to one nitrogen atom,

(xiv) a C₁₋₆ alkylcarbonylamino group,

(xv) a C₁₋₆ alkylsulfonylamino group,

(xvi) a C₁₋₆ alkoxycarbonyl group,

(xvii) a carboxyl group,

(xviii) a C₁₋₆ alkylcarbonyl group,

(xix) a carbamoyl group,

(xx) a mono- or di-C₁₋₆ alkylcarbamoyl group,

(xxi) a C₁₋₆ alkylsulfonyl group, or

(xxii) an oxo group;

the Ring B is a 5-membered to 6-membered aromatic group having from 1 to3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, inaddition to carbon atoms, a 5-membered to 9-membered non-aromaticheterocyclic group having from 1 to 3 hetero atoms selected fromnitrogen, oxygen and sulfur atoms, in addition to carbon atoms, or a3-membered to 10-membered cyclic hydrocarbon group each of which mayhave 1 to 4 substituents selected from

(i) a halogen atom,

(ii) a C₁₋₆ alkyl group optionally having from 1 to 5 substituentsselected from

(a) a hydroxyl group,

(b) an amino group,

(c) a carboxyl group,

(d) a nitro group,

(e) a mono- or di-C₁₋₆ alkylamino group,

(f) a C₁₋₆ alkyl-carbonyloxy group and

(g) a halogen atom,

(iii) an optionally halogenated C₁₋₆ alkoxy group,

(iv) an optionally halogenated C₁₋₆ alkylthio group,

(v) a C₆₋₁₀ aryl group,

(vi) a C₁₋₇ acylamino group,

(vii) a C₁₋₃ acyloxy group,

(viii) a hydroxy group,

(ix) a nitro group,

(x) a cyano group,

(xi) an amino group,

(xii) a mono- or di-C₁₋₆ alkylamino group,

(xiii) a 5-membered to 9-membered cyclicamino group which may have 1 to3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, inaddition to one nitrogen atom,

(xiv) a C₁₋₆ alkylcarbonylamino group,

(xv) a C₁₋₆ alkylsulfonylamino group,

(xvi) a C₁₋₆ alkoxycarbonyl group,

(xvii) a carboxyl group,

(xviii) a C₁₋₆ alkylcarbonyl group,

(xix) a carbamoyl group,

(xx) a mono- or di-C₁₋₆ alkylcarbamoyl group,

(xxi) a C₁₋₆ alkylsulfonyl group, and

(xxii) an oxo group;

the Ring C is a 5-membered to 10-membered heterocyclic group which mayhave 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atomswhich optionally having 1 to 5 substituents selected from

(i) a halogen atom,

(ii) an optionally halogenated C₁₋₁₀ alkyl group,

(iii) an amino-substituted C₁₋₄ alkyl group,

(vi) a mono- or di-C₁₋₄ alkylamino-substituted C₁₋₄ alkyl group,

(v) a carboxyl-substituted C₁₋₄ alkyl group,

(vi) a C₁₋₄ alkoxy-carbonyl-substituted C₁₋₄ alkyl group,

(vii) a hydroxy-substituted C₁₋₄ alkyl group,

(viii) a C₁₋₄ alkoxy-carbonyl-substituted C₁₋₄ alkyl group,

(ix) a C₃₋₁₀ cycloalkyl group,

(x) a nitro group,

(xi) a cyano group,

(xii) a hydroxyl group,

(xiii) an optionally-halogenated C₁₋₁₀ alkoxy group,

(xiv) an optionally-halogenated C₁₋₄ alkylthio group,

(xv) an amino group,

(xvi) a mono- or di-C₁₋₄ alkylamino group,

(xvii) a 5-membered to 9-membered cyclic amino group optionally having 1to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, inaddition to one nitrogen atom,

(xviii) a C₁₋₄ alkyl-carbonylamino group,

(xix) an aminocarbonyloxy group,

(xx) a mono- or di-C₁₋₄ alkylaminocarbonyloxy group,

(xxi) a C₁₋₄ alkylsulfonylamino group,

(xxii) a C₁₋₄ alkoxy-carbonyl group,

(xxiii) an aralkyloxycarbonyl group,

(xxiv) a carboxyl group,

(xxv) a C₁₋₆ alkyl-carbonyl group,

(xxvi) a C₃₋₆ cycloalkyl-carbonyl group,

(xxvii) a carbamoyl group,

(xxviii) a mono- or di-C₁₋₄ alkylcarbamoyl group,

(xxix) a C₁₋₆ alkylsulfonyl group and

(xxx) a 5-membered or 6-membered aromatic monocyclic heterocyclic grouphaving 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfuratoms, which may have 1 to 3 substituents selected from an optionallyhalogenated C₁₋₄ alkyl; or

a 3-membered to 10-membered cyclic hydrocarbon group, optionally having1 to 5 substituents selected from

(i) a halogen atom,

(ii) an optionally halogenated C₁₋₁₀ alkyl group,

(iii) an amino-substituted C₁₋₄ alkyl group,

(iv) a mono- or di-C₁₋₄ alkylamino-substituted C₁₋₄ alkyl group,

(v) a carboxyl-substituted C₁₋₄ alkyl group,

(vi) a hydroxy-substituted C₁₋₄ alkyl group,

(vii) a C₁₋₄ alkoxy-carbonyl-substituted C₁₋₄ alkyl group,

(viii) a C₃₋₁₀ cycloalkyl group,

(ix) a nitro group,

(x) a cyano group,

(xi) a hydroxyl group,

(xii) an optionally-halogenated C₁₋₁₀ alkoxy group,

(xiii) an optionally-halogenated C₁₋₄ alkylthio group,

(xiv) an amino group,

(xv) a mono- or di-C₁₋₄ alkylamino group,

(xvi) a 5-membered to 9-membered cyclic amino group optionally having 1to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, inaddition to one nitrogen atom,

(xvii) a C₁₋₄ alkyl-carbonylamino group,

(xviii) an aminocarbonyloxy group,

(xiv) a mono- or di-C₁₋₄ alkylaminocarbonyloxy group,

(xx) a C₁₋₄ alkylsulfonylamino group,

(xxi) a C₁₋₄ alkoxy-carbonyl group,

(xxii) an aralkyloxycarbonyl group,

(xxiii) a carboxyl group,

(xxiv) a C₁₋₆ alkyl-carbonyl group,

(xxv) a C₃₋₆ cycloalkyl-carbonyl group,

(xxvi) a carbamoyl group,

(xxvii) a mono- or di-C₁₋₄ alkylcarbamoyl group,

(xxviii) a C₁₋₆ alkylsulfonyl group and

(xxix) a 5-membered or 6-membered aromatic monocyclic heterocyclic grouphaving 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfuratoms, which may have 1 to 3 substituents selected from an optionallyhalogenated C₁₋₄ alkyl;

the Ring Z is a 5-membered to 12-membered heterocyclic ring optionallyhaving at least one hetero atom selected from nitrogen, oxygen andsulfur atoms, in addition to Y and the nitrogen atom, having 1 to 5substituents selected from

(i) a C₁₋₆ alkyl group,

(ii) a C₂₋₆ alkenyl group,

(iii) a C₂₋₆ alkynyl group,

(iv) a C₃₋₈ cycloalkyl group,

(v) a C₃₋₈ cycloalkyl-C₁₋₄ alkyl group,

(vi) a C₆₋₁₄ aryl group,

(vii) a nitro group,

(viii) a cyano group,

(ix) a hydroxyl group,

(x) a C₁₋₄ alkoxy group,

(xi) a C₁₋₄ alkylthio group,

(xii) an amino group,

(xiii) a mono- or di-C₁₋₄ alkylamino group,

(xiv) a 5-membered to 9-membered cyclic amino group optionally having 1to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, inaddition to one nitrogen atom,

(xv) a C₁₋₄ alkyl-carbonylamino group,

(xvi) a C₁₋₄ alkylsulfonylamino group,

(xvii) a C₁₋₄ alkoxy-carbonyl group,

(xviii) a carboxyl group,

(xix) a C₁₋₆ alkyl-carbonyl group,

(xx) a carbamoyl group,

(xxi) a mono- or di-C₁₋₄ alkylcarbamoyl group,

(xxii) a C₁₋₆ alkylsulfonyl group,

(xxiii) an oxo group, and

(xxiv) a thioxo group,

(3) A compound as described in (1), wherein R^(a) and R^(b) are bondedto each other to form Ring A, Ring C is an optionally substitutedbenzene ring or an optionally substituted heterocyclic ring, Ring Z is anitrogen-containing heterocyclic ring optionally substituted by an oxogroup, and n represents 1 or 2,

(4) A compound as described in (1), wherein Ring Z is anitrogen-containing heterocyclic ring optionally substituted by an oxogroup,

(5) A compound as described in (1), wherein one of Ring A and Ring B isan optionally substituted aromatic ring and the other is an optionallysubstituted aromatic heterocyclic ring,

(6) A compound as described in (1), wherein Ring A is an optionallysubstituted aromatic heterocyclic ring, and Ring B is an optionallysubstituted benzene ring,

(7) A compound as described in (6), wherein the aromatic heterocyclicring is a 5-membered or 6-membered, aromatic heterocyclic ring havingone or two hetero atoms selected from nitrogen, sulfur and oxygen atoms,in addition to carbon atoms,

(8) A compound as described in (1), wherein Ring C is an optionallysubstituted benzene ring,

(9) A compound as described in (1), wherein Ring C is a benzene ringwhich may have from 1 to 3 substituents selected from a halogen atom, anoptionally halogenated C₁₋₆ alkyl group and an optionally halogenatedC₁₋₆ alkoxy group,

(10) A compound as described in (1), wherein Ring Z is a 5-membered to10-membered ring optionally substituted by 1 or 2 oxo groups,

(11) A compound as described in (1), wherein --X . . . . . Y< is --N═CC<or --CO--N<,

(12) A compound as described in (1), wherein n is 1,

(13) A compound as described in (1), wherein Ring A is an optionallysubstituted pyridine ring, Ring B is an optionally substituted benzenering, Ring C is an optionally substituted benzene ring, Ring Z is a5-membered to 10-membered ring optionally substituted by an oxo group,--X . . . . . Y< is --CO--N<, and n is 1,

(14) A compound as described in (1), wherein R^(a) and R^(b) are thesame or different and represent, independently, a hydrogen atom, ahalogen atom, an optionally substituted alkyl group, an optionallyhalogenated alkoxy group, an optionally halogenated alkylthio group, acycloalkyl group, an aryl group, an acylamino group, an acyloxy group, ahydroxy group, a nitro group, a cyano group, an amino group, a mono- ordi-alkylamino group, a cyclic amino group, an alkylcarbonylamino group,an alkylsulfonylamino group, an alkoxycarbonyl group, a carboxyl group,an alkylcarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkylsulfonyl group or an oxo group,

(15) A compound as described in (1), wherein R^(a) and R^(b) are thesame or different and represent, independently,

(i) a hydrogen atom,

(ii) a C₁₋₆ alkoxy-C₁₋₆ alkyl group,

(iii) a C₁₋₆ alkylthio-C₁₋₆ alkyl group,

(iv) an amino-C₁₋₆ alkyl group,

(v) a C₁₋₇ acylamino-C₁₋₆ alkyl group,

(vi) a mono- or di-C₁₋₆ alkylamino-C₁₋₄ alkyl group,

(vii) C₃₋₁₀ cycloamino-C₁₋₆ alkyl group,

(viii) a C₁₋₆ alkyl group having 5-membered or 6-membered cycloaminooptionally substituted by C₁₋₆ alkyl group,

(ix) a C₁₋₆ alkylsulfonylamino-C₁₋₆ alkyl group, or

(x) a C₁₋₆ alkylcarbonyloxy-C₁₋₆ alkyl; or

R^(a) and R^(b) are bonded to each other to form pyridine ring which isoptionally substituted by 1 to 3 substituents selected from a halogenatom and a C₁₋₄ alkyl group;

Ring B is a benzene ring optionally having 1 to 3 substituents selectedfrom a halogen atom, an optionally halogenated C₁₋₄ alkyl group and anoptionally halogenated C₁₋₄ alkoxy group;

Ring C is a benzene ring optionally having 1 to 3 substituents selectedfrom a halogen atom, an optionally halogenated C₁₋₄ alkyl group, anoptionally halogenated C₁₋₄ alkoxy group, an amino group optionallysubstituted by C₁₋₄ alkyl group, a C₁₋₃ acyloxy group and a hydroxylgroup;

Ring Z is a 5-membered to 10-membered nitrogen containing heterocyclicring optionally having an oxo group and optionally substituted by a C₁₋₄alkyl group or a hydroxyl group; --X . . . . . Y< is --N═CC< or--CO--N<; and n is an integer of 1,

(16) A compound as described in (15), wherein R^(a) and R^(b) are bondedto each other to form Ring A, and --X . . . . . Y< is --CO--N<,

(17) A compound as described in (16), wherein the Ring A is anunsubstituted pyridine ring,

(18) A compound as described in (16), wherein the Ring B is a benzenering which optionally substituted by an optionally halogenated C₁₋₄alkyl group,

(19) A compound as described in (16), wherein the Ring C is an benzenering which may have 1 to 3 substituents selected from a halogen atom, anoptionally halogenated C₁₋₄ alkyl group and an optionally halogenatedC₁₋₄ alkoxy group,

(20) A compound as described in (16), wherein Ring Z is ##STR22##wherein, m and p are the same or different and represent, independently,an integer of from 1 to 5, Z₁ and Z₂ are the same or different andrepresent, independently, an hydrogen atom, an C₁₋₄ alkyl group or ahydroxyl group and Y is the same meaning as described in (15),

(21) A compound as described in (1), which is(9S)-7-[3,5-bis(trifluoromethyl)benzyl]-6,7,8,9,10,12-hexahydro-9-methyl-6,12-dioxo-5-phenyl[1,4]diazepino[2,1-g][1,7]naphthyridine,

(22) A compound as described in (1), which is(9s)-7-[3,5-bis(trifluoromethyl)benzyl]-6,7,8,9,10,12-hexahydro-9-methyl-5-(4-methylphenyl)-6,12-dioxo[1,4]diazepino[2,1-g][1,7]naphthyridine,

(23) A compound as described in (1), which is(9R)-7-[3,5-bis(trifluoromethyl)benzyl]-6,7,8,9,10,11-hexahydro-9-methyl-6,13-dioxo-5-phenyl-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine,

(24) A compound as described in (1), which is(9R)-7-[3,5-bis(trifluoromethyl)benzyl]-6,7,8,9,10,11-hexahydro-9-methyl-5-(4-methylphenyl)-6,13-dioxo-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine,

(25) A process for producing a compound as described in (1),characterized by cyclizing a compound of a formula: ##STR23## wherein Dand E represent groups from which ring Z as set forth in claim 1 isformed via the nitrogen atom adjacent to E, L represents a leavinggroup, and the other symbols are the same meanings as those described in(1), or a salt thereof,

(26) A pharmaceutical composition comprising a compound as described in(1),

(27) A composition for antagonizing tachykinin receptor compries acompound as described in (1),

(28) A composition for antagonizing Substance P receptor comprises acompound as described in (1),

(29) A composition for antagonizing neurokinin A receptor comprises acompound as described in (1),

(30) A pharmaceutical composition for preventing or treating disordersof micturition which comprises a compound as described in (1) and apharmaceutical acceptable carrier thereof,

(31) A pharmaceutical composition for preventing or treating disordersof asthma, rheumatoid arthritis, osteoarthritis, pain, migraine, cough,irritable bowel syndrome or emesis, which comprises a compound asdescribed in (1) and a pharmaceutical acceptable carrier thereof,

(32) A method for antagonizing tachykinin receptor in mammals whichcomprises administrating to a subject in need, an effective amount of acompound as described in (1),

(33) A method for preventing or treating disorders of micturition inmammals which comprises administrating to a subject in need an effectiveamount of a compound as described in (1),

(34) A method for preventing or treating disorders of asthma, migraine,irritable bowel syndrome, pain, cough or emesis in mammals whichcomprises administrating to a subject in need an effective amount of acompound as described in (1),

(35) Use of a compound as described in (1) for manufacturing acomposition for antagonizing a tachykinin receptor,

(36) Use of a compound as described in (1) for manufacturing apharmaceutical composition for treating disorders of micturition, and

(37) Use of a compound as described in (1) for manufacturing apharmaceutical composition for treating disorders of asthma,micturition, irritable bowel syndrome, pain, cough or emesis.

The compounds of the above-mentioned (1) include compounds of a formula(Ia): ##STR24## wherein ring A is formed by R^(a) and R^(b) are bondedto each other to form Ring A, and the other symbols have the samemeanings as above.

The present invention is described in detail hereinunder.

Regarding "Ring M, X and Y"

In the above-mentioned formulae (I) and (Ia), Ring M is a heterocyclicring having --N═C<, --CO--N< or --CS--N< as the partial structure "--X .. . . . Y<". Preferably, Ring M has --CO--N< or --N═C-- as the partialstructure "--X . . . . . Y<".

Regarding "R^(a) and R^(b) "

In the above-mentioned formulae (I) and (Ia), R^(a) and R^(b) are bondedto each other to form Ring A, or these are the same or different andrepresent, independently, a hydrogen atom or a substituent on the RingM.

The substituents R^(a) and R^(b) on the Ring M include, for example, ahalogen atom, an optionally substituted alkyl group, an optionallyhalogenated alkoxy group, an optionally halogenated alkylthio group, acycloalkyl group, an aryl group, an acylamino group, an acyloxy group, ahydroxyl group, a nitro group, a cyano group, an amino group, a mono- ordi-alkylamino group, a cyclic amino group (e.g., a cyclic amino groupoptionally containing hetero atom(s) of oxygen atom, sulfur atom, etc.,in addition to nitrogen atom), an alkylcarbonylamino group, analkylsulfonylamino group, an alkoxycarbonyl group, a carboxyl group, analkylcarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkylsulfonyl group, an oxo group, etc.

The above-mentioned "halogen atom" includes, for example, fluorine,chlorine, bromine and iodine atoms. Preferably, the halogen atomincludes, for example, fluorine, chlorine and bromine atoms.

The "optionally substituted alkyl group" includes, for example, C₁₋₆alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl groups, etc.) optionally having from 1 to 5substituents selected from a hydroxyl group, a C₁₋₆ alkoxy group (e.g.,methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,etc.), a C₁₋₆ alkylthio group (e.g., methylthio, ethylthio, propylthio,butylthio, isobutylthio, sec-butyltio, tert-butyltio, etc.), an aminogroup, a C₁₋₇ acylamino group (e.g. formylamino, acethyl amino,propyonyl amino, butylyl amino, benzoyl amino, etc.), an N-alkylaminogroup, a carboxyl group, a nitro group, a mono- or di-C₁₋₆ alkylaminogroup (e.g., methylamino, ethylamino, dimethylamino and diethylaminogroups, etc.), an optionally substituted N-substituted amino groupsubstituted by one or two homocyclic groups (e.g., mono- or di-C₃₋₈cycloalkylamino groups, for example, cyclopropylamino, cyclobutylamino,cyclohexylamino; C₆₋₁₀ arylamino groups, for example, phenylamino,etc.), an optionally substituted heterocyclic groups [e.g., 5-memberedto 9-membered cycloamino groups which may have 1 to 3 hetero atomsselected from nitrogen, oxygen and sulfur atoms (e.g., 5-membered or6-membered non-aromatic cycloamino groups, for example, piperidyno,4-methylpiperodyno, morpholino, thiomorpholino, piperadinyl,4-methylpiperadinyl, 4-ethylpiperadinyl, pyrrolidinyl, imidazolydinyl,pyrazolydinyl; 5-membered or 6-membered aromatic cycloamino groups, forexample, pyridyl, pyradyl, pyrimidinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazulyl, etc.), aromatic heterocyclic rings (e.g.,thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, etc.),non-aromatic heterocyclic rings (e.g., tetrohydropyridyl,dihydropyridyl, tetrahydropyradyl, tetrahydropyrimidinyl,tetrahydropyridazinyl, dihydropyranyl, dihydropyrrolyl,dyhydroimidazolyl, dihydropyrazolyl, dihydrothiophenyl, dihydrofuranyl,dihydrooxazolyl, dihydroisooxazolyl, hexahydropyrimidinyl,hexahydropyridazinyl, tetrahydropyranyl, pyrazolydinyl,tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrothiazolyl,tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl,etc.)], an alkylsulfonylamino groups (e.g. C₁₋₄ alkylsulfonylaminogroups, for example, methylsulfonylamino, ethylsulfonylamino, etc.), aC₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy and ethylcarbonyloxy groups,etc.) and a halogen atom (e.g., fluorine, chlorine and bromine atoms,etc.), etc. Preferably, the "optionally substituted alkyl group"includes C₁₋₆ alkyl groups optionally substituted by from 1 to 4 or sohalogen atoms, especially optionally halogenated C₁₋₄ alkyl groups(e.g., C₁₋₄ alkyl groups and C₁₋₄ alkyl groups substituted by from 1 to3 or so halogen atoms, etc., such as methyl, chloromethyl, fluoromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl,3,3,3-trifluoropropyl, isopropyl, 1-(trifluoromethyl)ethyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl and tert-butyl groups, etc.).Also preferably, the "optionally-substituted alkyl group" includes C₁₋₆alkoxy-C₁₋₆ alkyl groups (e.g. C₁₋₄ alkoxy-C₁₋₄ alkyl groups, forexample, methoxymethyl, ethoxymethyl, isopropoxymethyl, butoxymethyl,methoxyethyl, ethoxyethyl, etc.), C₁₋₆ alkyltho-C₁₋₆ alkyl groups (e.g.C₁₋₄ alkylthio-C₁₋₄ alkyl groups, for example, methylthiomethyl,ethylthiomethyl, butylthiomethyl, methylthioethyl, ethylthioethyl,etc.), amino-C₁₋₆ alkyl groups (preferably, amino-C₁₋₄ alkyl groups),for example, aminomethyl, 2-aminoethyl, 2-aminopropyl, 3-aminopropyl,2-aminobutyl, 3-aminobutyl and 4-aminobutyl groups, C₁₋₇ acylamino-C₁₋₆alkyl groups (e.g. C₁₋₇ acylamino-C₁₋₄ alkyl groups, for example,formylaminomethyl, acetylaminomethyl, propionylaminomethyl,butylylaminoethyl, benzoylaminomethyl, etc.), etc. And, again, the"optionally-substituted alkyl group" preferably includes mono-C₁₋₄alkylamino-C₁₋₆ alkyl groups, for example, mono-C₁₋₃ alkylamino-C₁₋₄alkyl groups, etc., such as methylaminomethyl, ethylaminomethyl,2-(N-methylamino)ethyl, 2-(N-ethylamino)ethyl, 2-(N-methylamino)propyl,3-(N-methylamino)propyl, 3-(N-methylamino)butyl and4-(N-methylamino)butyl groups, C₃₋₁₀ cycloalkylamino-C₁₋₆ alkyl groups(e.g. C₃₋₁₀ cycloalkylamino-C₁₋₄ alkyl groups, for example,cyclopropylaminomethyl, cyclobutylaminomethyl, cyclohexylaminomethyl,cyclopropylaminomethyl, cyclobutylaminomethyl, cyclohexylaminomethyl,phenylaminomethyl, etc.), optionally having 1 to 3 hetero atoms selectedfrom nitrogen, oxygen and sulfur atoms 5-membered or 6-memberednon-aromatic cycloamino-C₁₋₆ alkyl groups (e.g. 5-membered or 6-memberednon-aromatic cycloamino-C₁₋₄ alkyl groups, for example,piperidinomethyl, 4-methylpiperidinomethyl, morpholinomethyl,thiomorpholinomethyl, piperadinylmethyl, 4-methylpiperadinylmethyl,piperidinoethyl, morpholinoethyl, piperadinylethyl; 5-membered or6-membered aromatic cycloamino-C₁₋₄ alkyl groups, for example,pyridylmethyl, pyrimidinylmethyl, imidazolylmethyl, pyridylethyl, etc.),C₁₋₆ alkylsulfonylamino-C₁₋₆ alkyl groups (e.g. C₁₋₆alkylsulfonylamino-C₁₋₄ alkyl groups, for example,methylsulfonylaminomethyl, ethylsulfonylaminomethyl,methylsulfonylaminobutyl, ethylsulfonylaminoethyl, etc.), C₁₋₆alkyl-carbonyloxy-C₁₋₆ alkyl groups (e.g. C₁₋₄ alkyl-carbonyloxy-C₁₋₄alkyl groups, for example, methylcarbonyloxymethyl,ethylcarbonyloxymethyl, butylcarbonyloxymethyl, methylcarbonyloxyethyl,ethylcarbonyloxyethyl, etc.), etc.

The "optionally halogenated alkoxy group" includes, for example, C₁₋₆alkoxy groups or C₁₋₆ alkoxy groups substituted by from 1 to 5 or sohalogen atoms, etc. Such alkoxy groups or halogenated alkoxy groupsinclude, for example, methoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy,2,2,2-trichloroethoxy, pentafluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy and hexyloxygroups, etc. Preferably, the "optionally-halogenated alkoxy group"includes C₁₋₄ alkoxy groups or C₁₋₄ alkoxy group substituted by from 1to 3 or so halogen atoms, for example, methoxy, difluoromethoxy,trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,butoxy, 4,4,4-trifluorobutoxy, isobutoxy and sec-butoxy groups, etc.

The "optionally halogenated alkylthio group" includes, for example, C₁₋₆alkylthio groups, and C₁₋₆ alkylthio groups having from 1 to 5 or sohalogen atoms, etc. Such alkylthio groups and halogenated alkylthiogroups include, for example, methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio and hexylthio groups, etc.Preferably, the "optionally halogenated alkylthio group" includes C₁₋₄alkylthio groups, or C₁₋₄ alkylthio groups substituted by from 1 to 3 orso halogen atoms, for example, methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio and4,4,4-trifluorobutylthio groups, etc.

The "cycloalkyl group" includes C₃₋₁₀ cycloalkyl groups (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl groups,etc.); the "aryl group" includes C₆₋₁₀ aryl groups (e.g., phenyl group,etc.); the "acylamino group" includes, for example, C₁₋₇ acylaminogroups (e.g., formylamino, acetylamino, propionylamino, butyrylamino andbenzoylamino groups, etc.), etc. The "acyloxy group" includes, forexample, C₁₋₃ acyloxy groups (e.g., formyloxy, acetoxy and propionyloxygroups, etc.), etc. The "mono- or di-alkylamino group" includes, forexample, mono- or di-C₁₋₄ alkylamino groups (e.g., methylamino,ethylamino, propylamino, dimethylamino and diethylamino groups, etc.),etc. The "cyclic amino group" includes, for example, 5-membered to9-membered cyclic amino groups optionally having from 1 to 3 heteroatoms, such as oxygen atom, sulfur atom, etc., in addition to nitrogenatom (e.g., pyrrolidino, piperidino, morpholino and thiomorpholinogroups, etc.), etc. The "alkylcarbonylamino group" includes, forexample, C₁₋₄ alkyl-carbonylamino groups (e.g., acetylamino,propionylamino and butyrylamino groups, etc.); the "alkylsulfonylaminogroup" includes, for example, C₁₋₄ alkylsulfonylamino groups (e.g.,methylsulfonylamino and ethylsulfonylamino groups, etc.); the"alkoxycarbonyl group" includes, for example, C₁₋₄ alkoxy-carbonylgroups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl andbutoxycarbonyl groups, etc.); the "alkylcarbonyl group" includes, forexample, C₁₋₆ alkyl-carbonyl groups (e.g., methylcarbonyl, ethylcarbonyland propylcarbonyl groups, etc.); the "mono- or di-alkylcarbamoyl group"includes for example, mono- or di-C₁₋₄ alkylcarbamoyl groups (e.g.,methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl and diethylcarbamoylgroups, etc.); the "alkylsulfonyl group" includes, for example, C₁₋₆alkylsulfonyl groups (e.g., methylsulfonyl, ethylsulfonyl andpropylsulfonyl groups, etc.), etc.

Regarding "Ring A and Ring B"

In the above-mentioned formulae (I) and (Ia), Ring A and Ring Brepresent, independently, an optionally substituted homocyclic orheterocyclic ring, and at least one of these is an optionallysubstituted heterocyclic ring.

The "homocyclic or heterocyclic ring" includes, for example, (i) anaromatic heterocyclic ring or non-aromatic heterocyclic ring having thesame one or different hetero atoms selected from nitrogen, sulfur andoxygen atoms, preferably from 1 to 3 such hetero atoms, in addition tocarbon atoms, or (ii) a cyclic hydrocarbon ring (homocyclic ring)comprising carbon atoms, etc.

The "aromatic heterocyclic ring" includes, for example, 5-membered or6-membered aromatic heterocyclic rings having from 1 to 3 hetero atomsselected from nitrogen, oxygen and sulfur atoms, in addition to carbonatoms (e.g., pyridine, pyrazine, pyrimidine, pyridazine, pyrrole,imidazole, pyrazole, triazole, thiophene, furan, thiazole, isothiazole,oxazole and isoxazole rings, etc.), etc. Preferably, the aromaticheterocyclic ring includes, for example, pyridine, pyrazine andthiophene rings, etc., as well as pyrrole and thiazole rings, etc.Especially preferred are (i) 6-membered, nitrogen-containingheterocyclic rings having one or two nitrogen atoms in addition tocarbon atoms (e.g., pyridine and pyrazine rings, etc.) or (ii)5-membered aromatic heterocyclic rings having one sulfur atom inaddition to carbon atoms (e.g., thiophene ring, etc.), etc.

The "non-aromatic heterocyclic ring" includes, for example, 5-memberedto 9-membered, non-aromatic heterocyclic rings, preferably 5-membered or6-membered, non-aromatic heterocyclic rings, having from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition tocarbon atoms, etc.

For example, Ring A includes tetrahydropyridine, dihydropyridine,tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine,dihydropyran, dihydropyrrole, dihydroimidazole, dihydropyrazole,dihydrothiophene, dihydrofuran, dihydrothiazole, dihydroisothiazole,dihydroxazole and dihydroisoxazole rings, etc.; and Ring A includes, inaddition to these rings, piperidine, piperazine, hexahydropyrimidine,hexahydropyridazine, tetrahydropyran, morpholine, pyrrolidine,imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran,tetrahydrothiazole, tetrahydroisothiazole, tetrahydroxazole andtetrahydroisoxazole rings, etc. Preferably, Ring A includes, forexample, 6-membered, non-aromatic heterocyclic rings having one or twonitrogen atoms in addition to carbon atoms (e.g., tetrahydropyridine,tetrahydropyrimidine and tetrahydropyridazine rings, etc.), etc., and isespecially preferably a tetrahydropyridine ring, etc. Preferably, Ring Bincludes, for example, 6-membered, non-aromatic heterocyclic ringshaving one or 2 nitrogen atoms in addition to carbon atoms (e.g.,piperidine and piperazine rings, etc.), etc., and is especiallypreferably a piperazine ring, etc.

The "cyclic hydrocarbon ring (homocyclic ring)" includes, for example,3-membered to 10-membered (for example, 5-membered to 9-membered) cyclichydrocarbon rings, preferably 5-membered or 6-membered cyclichydrocarbon rings, etc. For example, Ring A includes benzene, C₃₋₁₀cycloalkenes (e.g., cyclobutene, cyclopentene, cyclohexene,cycloheptene, cyclooctene, etc.), etc. The cycloalkenes are preferablyC₅₋₆ cycloalkenes (e.g., cyclopentene, cyclohexene, etc.), etc. Ring Bincludes, in addition to these, C₃₋₁₀ cycloalkanes (e.g., cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.), etc. Thecycloalkanes are preferably C₅₋₆ cycloalkanes (e.g., cyclohexane,cyclopentane, etc.), etc. Preferably, Ring A includes, for example,6-membered homocyclic rings such as benzene and cyclohexene rings, etc.Especially preferred are a benzene ring, etc. Ring B preferablyincludes, for example, 6-membered homocyclic rings such as benzene andcyclohexane rings, etc. Especially preferred is a benzene ring.

At least one of Ring A and Ring B is an optionally-substitutedheterocyclic ring. Both of Ring A and Ring B may be optionallysubstituted heterocyclic rings. Preferably, one of Ring A and Ring Bis 1) an optionally substituted aromatic ring and the other is 2) anoptionally substituted aromatic heterocyclic ring.

The above-mentioned 1) "aromatic ring" includes, for example, (i) theabove-mentioned "aromatic heterocyclic rings", namely, optionallysubstituted, 5-membered or 6-membered, aromatic heterocyclic ringshaving the same one or different two hetero atoms selected fromnitrogen, sulfur and oxygen atoms, preferably from 1 to 3 such heteroatoms, in addition to carbon atoms (e.g., pyridine, pyrazine,pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole,thiophene, furan, thiazole, isothiazole, oxazole and isoxazole rings,etc.), or (ii) optionally substituted benzene rings.

For the substituents for the above-mentioned 1) "optionally substitutedaromatic ring", for example, referred to are the same substituents asthose for Ring A and Ring B which are mentioned hereinunder. The"aromatic heterocyclic ring" of the above-mentioned 2) "optionallysubstituted aromatic heterocyclic ring" includes, for example, the samearomatic heterocyclic rings as those in the above-mentioned "5-memberedor 6-membered, aromatic heterocyclic ring". For the substituents for theabove-mentioned 2) "optionally substituted aromatic heterocyclic ring",for example, referred to are the same substituents as those for Ring Aand Ring B which are mentioned hereinunder. The "5-membered or6-membered, aromatic heterocyclic ring" preferably includes the sameheterocyclic rings as those referred to hereinabove for the foregoing"aromatic heterocyclic ring".

More preferably, one of Ring A and Ring B is an optionally substitutedaromatic heterocyclic ring (e.g., a 5-membered or 6-membered aromaticheterocyclic ring) and the other is an optionally substituted benzenering.

The substituents for the optionally substituted "homocyclic orheterocyclic ring", "aromatic heterocyclic ring", "non-aromaticheterocyclic ring", "cyclic hydrocarbon ring", "aromatic ring" and"benzene ring" to be represented by Ring A and Ring B include, forexample, a halogen atom, an optionally substituted alkyl group, anoptionally halogenated alkoxy group, an optionally halogenated alkylthiogroup, an aryl group, an acylamino group, an acyloxy group, a hydroxylgroup, a nitro group, a cyano group, an amino group, a mono- ordi-alkylamino group, a cyclic amino group (e.g., a cyclic amino groupoptionally having hetero atom selected from oxygen atom, sulfur atom,etc., in addition to nitrogen atom), an alkylcarbonylamino group, analkylsulfonylamino group, an alkoxycarbonyl group, a carboxyl group, analkylcarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkylsulfonyl group, an oxo group, etc.

The "halogen atom", which Ring A and Ring B may have, includes, forexample, fluorine, chlorine, bromine and iodine atoms. Preferably, thehalogen atom includes, for example, fluorine, chlorine and bromine atoms(especially, fluorine and chlorine atoms, etc.).

The "optionally substituted alkyl group", which Ring A and Ring B mayhave, includes, for example, C₁₋₆ alkyl groups (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups,etc.) optionally having from 1 to 5 substituents selected from ahydroxyl group, an amino group, a carboxyl group, a nitro group, a mono-or di-C₁₋₆ alkylamino group (e.g., methylamino, ethylamino,dimethylamino and diethylamino groups, etc.), a C₁₋₆ alkyl-carbonyloxygroup (e.g., acetoxy and ethylcarbonyloxy groups, etc.) and a halogenatom (e.g., fluorine, chlorine and bromine atoms, etc.), etc. Especiallypreferred are optionally-halogenated alkyl groups, for example, C₁₋₆alkyl groups, and C₁₋₆ alkyl groups substituted by from 1 to 4 or sohalogen atoms, etc. Such alkyl groups and halogenated alkyl groupsinclude, for example, methyl, chloromethyl, fluoromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl,3,3,3-trifluoropropyl, isopropyl, 1-(trifluoromethyl)ethyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, 5,5,5-trifluoropentyl, 4-trifluoromethylbutyl,hexyl, 6,6,6-trifluorohexyl and 5-trifluoromethylpentyl groups, etc.

More preferably, the "optionally substituted alkyl group" includesoptionally halogenated C₁₋₄ alkyl groups, for example, C₁₋₄ alkyl groupsand C₁₋₄ alkyl groups substituted by from 1 to 3 or so halogen atoms,etc., such as methyl, chloromethyl, difluoromethyl, trichloromethyl,trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl,2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyland tert-butyl groups, etc.

The "optionally halogenated alkoxy group", which Ring A and Ring B mayhave, includes, for example, C₁₋₆ alkoxy groups or C₁₋₆ alkoxy groupssubstituted by from 1 to 5 or so halogen atoms such as those mentionedhereinabove, etc. Such alkoxy groups or halogenated alkoxy groupsinclude, for example, methoxy, difluoromethoxy, trifluoromethoxy,trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy,pentafluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy,isobutoxy, sec-butoxy, pentoxy and hexyloxy groups, etc. Preferably, the"optionally halogenated alkoxy group" includes C₁₋₄ alkoxy groups orC₁₋₄ alkoxy group substituted by from 1 to 3 or so halogen atoms, forexample, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy and sec-butoxy groups, etc.

The "optionally halogenated alkylthio group", which Ring A and Ring Bmay have, includes, for example, C₁₋₆ alkylthio groups, and C₁₋₆alkylthio groups having from 1 to 5 or so halogen atoms such as thosementioned hereinabove, etc. Such alkylthio groups and halogenatedalkylthio groups include, for example, methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio and hexylthio groups, etc.Preferably, the "optionally halogenated alkylthio group" includes C₁₋₄alkylthio groups, or C₁₋₄ alkylthio groups substituted by from 1 to 3 orso halogen atoms, for example, methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio and4,4,4-trifluorobutylthio groups, etc.

The aryl group as the substituent includes C₆₋₁₀ aryl groups (e.g.,phenyl group, etc.); the acylamino group includes, for example, C₁₋₇acylamino groups (e.g., formylamino, acetylamino, propionylamino,butyrylamino and benzoylamino groups, etc.), etc. The acyloxy groupincludes, for example, C₁₋₃ acyloxy groups (e.g., formyloxy, acetoxy andpropionyloxy groups, etc.), etc. The mono- or di-alkylamino groupincludes, for example, mono- or di-C₁₋₄ alkylamino groups (e.g.,methylamino, ethylamino, propylamino, dimethylamino and diethylaminogroups, etc.), etc. The cyclic amino group includes, for example,5-membered to 9-membered cyclic amino groups optionally having from 1 to3 hetero atoms, such as oxygen atom, sulfur atom, etc., in addition tonitrogen atom (e.g., pyrrolidino, piperidino and morpholino groups,etc.), etc. The alkylcarbonylamino group includes, for example, C₁₋₄alkyl-carbonylamino groups (e.g., acetylamino, propionylamino andbutyrylamino groups, etc.); the alkylsulfonylamino group includes, forexample, C₁₋₄ alkylsulfonylamino groups (e.g., methylsulfonylamino andethylsulfonylamino groups, etc.); the alkoxycarbonyl group includes, forexample, C₁₋₄ alkoxy-carbonyl groups (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl groups, etc.); thealkylcarbonyl group includes, for example, C₁₋₆ alkyl-carbonyl groups(e.g., methylcarbonyl, ethylcarbonyl and propylcarbonyl groups, etc.);the mono- or di-alkylcarbamoyl group includes, for example, mono- ordi-C₁₋₄ alkylcarbamoyl groups (e.g., methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl and diethylcarbamoyl groups, etc.); the alkylsulfonylgroup includes, for example, C₁₋₆ alkylsulfonyl groups (e.g.,methylsulfonyl, ethylsulfonyl and propylsulfonyl groups, etc.), etc.

The terminology "optionally halogenated" as referred to herein meansthat the number of halogen atoms, if substituted, is from 1 to 5,preferably from 1 to 3 or so.

Preferred substituents for the optionally substituted Ring A and Ring Binclude a halogen atom, an optionally halogenated C₁₋₄ alkyl group, anoptionally halogenated C₁₋₄ alkoxy group, an optionally halogenated C₁₋₄alkylthio group, a C₁₋₃ acyloxy group, a hydroxyl group, an amino group,a mono- or di-C₁₋₄ alkylamino group, a carboxyl group, a C₁₋₄alkoxy-carbonyl group, an oxo group, etc.

More preferred substituents for the optionally substituted Ring A andRing B include a halogen atom, an optionally halogenated C₁₋₄ alkylgroup, an optionally halogenated C₁₋₄ alkoxy group, a hydroxyl group, anamino group, a mono- or di-C₁₋₄ alkylamino group, a C₁₋₃ acyloxy group,an oxo group, etc. Especially preferred are a halogen atom, anoptionally halogenated C₁₋₄ alkyl group, an optionally halogenated C₁₋₄alkoxy group, etc.

The substituents for Ring A and Ring B, if any, may be at anysubstitutable position. If the rings are substituted by two or moresubstituents, the substituents may be the same or different. The numberof the substituents may be from 1 to 4 or so, preferably from 1 to 3 orso.

If the Ring A and/or the Ring B has nitrogen atom(s), the ring may forma quaternary salt. For example, it may form a salt with halide ion(s)(e.g., Cl⁻, Br⁻, I⁻, etc.) or other anion(s) such as sulfato ion,hydroxyl ion, etc.

Regarding "Ring A"

Preferred homocyclic rings for Ring A are optionally substitutedhomocyclic rings composed of carbon atoms, for example, including thoseof a formula (A-1): ##STR25## wherein . . . . . indicates a single bondor a double bound and the same shall apply hereinunder; and A¹represents a halogen atom (e.g., fluorine and chlorine atoms, etc.), anoptionally-halogenated C₁₋₄ alkyl group (e.g., methyl, isopropyl,trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl andpentafluoroethyl groups, etc.), or an optionally halogenated C₁₋₄ alkoxygroup (e.g., methoxy, trifluoromethoxy, trichloromethoxy, ethoxy,2,2,2-trifluoroethoxy and pentafluoroethoxy groups, etc.); or those of aformula (A-2): ##STR26## wherein A² and A³ are the same or different andrepresent, independently, a halogen atom (e.g., fluorine and chlorineatoms, etc.), an optionally halogenated C₁₋₄ alkyl group (e.g., methyl,isopropyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyland pentafluoroethyl groups, etc.), or an optionally halogenated C₁₋₄alkoxy group (e.g., methoxy, trifluoromethoxy, trichloromethoxy, ethoxy,2,2,2-trifluroroethoxy and pentafluoroethoxy groups, etc.).

More preferred homocyclic rings include, for example, benzene rings of aformula (A-3): ##STR27## wherein A⁴ and A⁵ are the same or different andrepresent, independently, a halogen atom (e.g., fluorine and chlorineatoms, etc.), or an optionally-halogenated C₁₋₄ alkyl group (e.g.,methyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl,pentafluoroethyl and isopropyl groups, etc.).

Also preferred are optionally substituted benzene rings of a formula(A-4): ##STR28## wherein the symbols have the same meanings as above.

Of the homocyclic rings of the above-mentioned formulae, especiallypreferred are those as substituted by the following substituent(s):

(1) Homocyclic rings where A¹ is a halogen atom (e.g., fluorine andchlorine atoms, etc.), or an optionally-substituted C₁₋₄ alkyl group(e.g., methyl, trifluoromethyl, ethyl and isopropyl groups, etc.).

(2) Homocyclic rings where A² and A³ are the same or different andrepresent, independently, an optionally-halogenated C₁₋₄ alkyl group(e.g., methyl, trifluoromethyl, ethyl and isopropyl groups, etc.), or anoptionally-halogenated C₁₋₄ alkoxy group (e.g., methoxy,trifluoromethoxy and ethoxy groups, etc.).

(3) Homocyclic rings where A⁴ and A⁵ are the same or different andrepresent, independently, a C₁₋₄ alkyl group (e.g., methyl, ethyl andisopropyl groups, etc.).

(4) Homocyclic rings where A¹ is a halogen atom (e.g., fluorine andchlorine atoms, etc.).

(5) Homocyclic rings where A² and A³ are the same or different andrepresent, independently, a C₁₋₄ alkoxy group (e.g., methoxy and ethoxygroups, etc.).

Preferred aromatic heterocyclic or non-aromatic heterocyclic rings forRing A are 5-membered or 6-membered, aromatic heterocyclic ornon-aromatic heterocyclic rings including, for example, pyridine,pyrazine, thiophene, tetrahydropyridine, pyrrole and thiazole rings,etc. Concretely, for example, preferred are heterocyclic rings of aformula (A-5): ##STR29##

As preferred examples of optionally substituted aromatic or non-aromaticheterocyclic rings for Ring A, mentioned are pyridine, pyrazine,thiophene, tetrahydropyridine, pyrrole and thiazole rings, etc.optionally having one or two substituents selected from an oxo group, anoptionally substituted alkyl group (this has the same meaning as thesubstituent for the optionally substituted Ring A and Ring B), a C₆₋₁₀aryl group (e.g., phenyl group, etc.) and a halogen atom (e.g.,fluorine, chlorine and bromine atoms, etc.). Concretely, for example,preferred are aromatic or non-aromatic heterocyclic rings of a formula(A-6): ##STR30## wherein D¹ represents a hydrogen atom, a halogen atom(e.g., fluorine, chlorine and bromine atoms, etc.); E¹ represents a C₁₋₄alkyl group (e.g., methyl, ethyl, propyl and isopropyl groups, etc.);the compounds having the partial structure of (ii) form quaternaryammonium salts along with a halide ion (e.g., Cl⁻, Br⁻, I⁻, etc.), asulfato ion, a hydroxyl ion or the like; G represents a hydrogen atom ora C₁₋₄ alkyl group (e.g., methyl, ethyl, propyl and isopropyl groups,etc.); J represents a hydrogen atom, a C₁₋₄ alkyl group (e.g., methyl,ethyl, propyl and isopropyl groups, etc.) or a C₆₋₁₀ aryl group (e.g.,phenyl group, etc.).

More preferably, ring A is a pyridine ring which may be substituted by 1to 3 substituents selected from a halogen atom or C₁₋₄ alkyl group.

Ring A is preferably a 5-membered or a 6-membered, nitrogen-containingheterocyclic ring, for example, (i) a 6-membered, aromatic,nitrogen-containing heterocyclic ring having one or two nitrogen atomsin addition to carbon atoms (e.g., pyridine and pyrazine rings, etc.),(ii) a 6-membered, non-aromatic heterocyclic ring having one or twonitrogen atoms in addition to carbon atoms (e.g., tetrahydropyridine,tetrahydropyrimidine and tetrahydropyridazine rings, etc.), or the like.Especially preferably, Ring A is an aromatic, nitrogen-containingheterocyclic ring, particularly, a pyridine ring or the like.

Regarding "Ring B"

Preferred homocyclic rings for Ring B are optionally substitutedhomocyclic rings composed or carbon atoms, for example, including thoseof a formula (B-1): ##STR31## wherein B¹ represents a halogen atom, anoptionally halogenated C₁₋₄ alkyl group or an optionally halogenatedC₁₋₄ alkoxy group; those of a formula (B-2): ##STR32## wherein B² and B³are the same or different and represent, independently, a halogen atom,an optionally halogenated C₁₋₄ alkyl group or an optionally halogenatedC₁₋₄ alkoxy group; and those of a formula (B-3): ##STR33## wherein B⁴,B⁵ and B⁶ are the same or different and represent, independently, ahalogen atom, an optionally halogenated C₁₋₄ alkyl group or anoptionally halogenated C₁₋₄ alkoxy group.

More preferred are homocyclic rings of a formula (B-4): ##STR34##wherein B⁷, B⁸ and B⁹ are the same or different and represent,independently, a halogen atom, an optionally halogenated C₁₋₄ alkylgroup or an optionally halogenated C₁₋₄ alkoxy group.

Even more preferred are homocyclic rings of a formula (B-5): ##STR35##wherein B¹⁰ represents, a halogen atom, an optionally halogenated C₁₋₄alkyl group or an optionally halogenated C₁₋₄ alkoxy group.

In the above-mentioned formulae, the halogen atom for any of B¹ to B¹⁰includes, for example, fluorine, chlorine and bromine atoms, etc.; theoptionally-halogenated C₁₋₄ alkyl group includes, for example, methyl,trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl,2,2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl,propyl, 2,2,3,3-tetrafluoropropyl and isopropyl groups, etc.; and theoptionally-halogenated C₁₋₄ alkoxy group includes, for example, methoxy,trifluoromethoxy, trithloromethoxy, ethoxy, 2,2,2-trifluoroethoxy,2,2,2-trichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy,propoxy, 2,2,3,3-tetrafluoropropoxy and isopropoxy groups, etc.

Ring B is also preferably an optionally substituted benzene ring, whichincludes, for example, benzene rings of a formula (B-6): ##STR36##

More preferred are benzene rings of a formula (B-7): ##STR37##

Especially preferred are benzene rings of a formula (B-8): ##STR38##

In these formulae, the symbols have the same meanings as above.

Of the substituents in the above-mentioned formulae, for example,especially preferred are the following:

(1) B¹, B², B³, B⁴, B⁵ and B⁶ are the same or different and represent,independently, a halogen atom (e.g., fluorine and chlorine atoms, etc.)or an optionally halogenated C₁₋₄ alkyl group (e.g., methyl,trifluoromethyl, ethyl and isopropyl groups, etc.).

(2) B¹, B², B³, B⁴, B⁵ and B⁶ are the same or different and represent,independently, an optionally-halogenated C₁₋₄ alkoxy group (e.g.,methoxy, trifluoromethoxy and ethoxy groups, etc.).

(3) B⁷, B⁸ and B⁹ represent halogen atoms (e.g., fluorine and chlorineatoms, etc.).

(4) B¹⁰ represents a fluorine atom.

(5) B¹⁰ represents a C₁₋₄ alkyl group (e.g., methyl group, etc.).

More preferred optionally substituted benzene rings are phenyl groups ofa formula (B-9): ##STR39##

As preferred examples of aromatic heterocyclic rings or non-aromaticheterocyclic rings for Ring B, mentioned are 5-membered or 6-memberedaromatic heterocyclic rings or non-aromatic heterocyclic rings such aspyridine, thiophene and piperidine rings, etc. These rings mayoptionally be substituted by substituents such as those mentionedhereinabove as preferred substituents for Ring A.

Where Ring B is an aromatic heterocyclic ring or a non-aromaticheterocyclic ring, it especially preferably includes, for example,heterocyclic rings of a formula (B-10): ##STR40## Combination of Ring Aand Ring B

Where one or both of Ring A and Ring B is/are heterocyclic ring(s), thering(s) is/are also preferably unsubstituted one(s).

Preferred combinations of Ring A and Ring B (1) are as follows:

(1) One of Ring A and Ring B is a 5-membered or 6-membered heterocyclicring having one or two hetero atoms selected from nitrogen and sulfuratoms in addition to carbon atoms (e.g., pyridine, pyrazine, thiophene,tetrahydropyridine, piperidine and piperazine rings, etc.) which may beoptionally substituted by C₁₋₄ alkyl group(s) (e.g., methyl, ethyl andisopropyl groups, etc.).

One of Ring A and Ring B is a benzene ring optionally substituted byfrom 1 to 3 substituents selected from a halogen atom (e.g., fluorine,chlorine and bromine atoms, etc.), an optionally halogenated C₁₋₄ alkylgroup (e.g., methyl, trifluoromethyl, trichloromethyl, ethyl,2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,2-trichloroethyl, propyl andisopropyl groups, etc.) and an optionally halogenated C₁₋₄ alkoxy group(e.g., methoxy, trifluoromethoxy, trichloromethoxy, ethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,2-trichloroethoxy, propoxyand isopropoxy groups, etc.).

More preferred combinations of Ring A and Ring B (2) are as follows:

(2) One of Ring A and Ring B is a 5-membered or 6-membered aromaticheterocyclic ring having one or two hetero atoms selected from nitrogenand sulfur atoms in addition to carbon atoms (e.g., pyridine, pyrazineand thiophene rings, etc.).

One of Ring A and Ring B is a benzene ring optionally substituted byfrom 1 to 3 substituents selected from a halogen atom (e.g., fluorine,chlorine and bromine atoms, etc.), an optionally halogenated C₁₋₄ alkylgroup (e.g., methyl, trifluoromethyl, trichloromethyl, ethyl,2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,2-trichloroethyl, propyl andisopropyl groups, etc.) and an optionally halogenated C₁₋₄ alkoxy group(e.g., methoxy, trifluoromethoxy, trichloromethoxy, ethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,2-trichloroethoxy, propoxyand isopropoxy groups, etc.).

Especially preferably, Ring A is an optionally substituted aromaticheterocyclic ring such as that mentioned above (e.g., an optionallysubstituted, 5-membered or 6-membered aromatic heterocyclic ring,especially pyridine ring, etc.) while Ring B is an optionallysubstituted benzene ring.

Regarding "Ring C"

In the above-mentioned formulae (I) and (Ia), Ring C represents anoptionally substituted homocyclic ring or an optionally substitutedheterocyclic ring. The homocyclic ring or the heterocyclic ring may havefrom 1 to 5 or so, preferably from 1 to 3 or so substituents, which maybe the same or different. The substituents may be positioned at anyposition of the homocyclic or heterocyclic ring.

The homocyclic ring includes "cyclic hydrocarbon (homocyclic) rings"such as those as referred to hereinabove for "Ring A and Ring B", forexample, from 3-membered to 10-membered cyclic hydrocarbon rings,preferably 5-membered or 6-membered cyclic hydrocarbon rings, such asbenzene, C₃₋₁₀ cycloalkenes (e.g., cyclobutene, cyclopentene,cyclohexene, cycloheptene, cyclooctene, etc.), C₃₋₁₀ cycloalkanes (e.g.,cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane,etc.), etc. of these, preferred are 6-membered homocyclic rings, such asbenzene, cyclohexene and cyclohexane rings, etc. Especially preferred isbenzene ring.

The substituents for the above-mentioned benzene ring and otherhomocyclic rings include, for example, a halogen atom (e.g., fluorine,chlorine, bromine and iodine atoms), an optionally-halogenated C₁₋₁₀alkyl group (e.g., methyl, chloromethyl, difluoromethyl trichloromethyl,trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,perfluoroethyl, propyl, isopropyl, 3,3,3-trifluoropropyl, butyl,isobutyl, t-butyl, perfluorobutyl, pentyl, hexyl, octyl and decylgroups, etc.), an amino-substituted C₁₋₄ alkyl group (e.g., aminomethyland 2-aminoethyl groups, etc.), a mono- or di-C₁₋₄alkylamino-substituted C₁₋₄ alkyl group (e.g., methylaminomethyl,dimethylaminomethyl, 2-aminoethyl and 2-dimethylaminoethyl groups,etc.), a carboxyl-substituted C₁₋₄ alkyl group (e.g., carboxymethyl andcarboxyethyl groups, etc.), a C₁₋₄ alkoxy-carbonyl-substituted C₁₋₄alkyl group (e.g., methoxycarbonylethyl and ethoxycarbonylethyl groups,etc.), a hydroxyl-substituted C₁₋₄ alkyl group (e.g., hydroxymethyl andhydroxyethyl groups, etc.), a C₁₋₄ alkoxy-carbonyl-substituted C₁₋₄alkyl group (e.g., methoxymethyl, ethoxyethyl and ethoxyethyl groups,etc.), a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups, etc.), anitro group, a cyano group, a hydroxyl group, an optionally-halogenatedC₁₋₁₀ alkoxy group (e.g., methoxy, difluoromethoxy, trichloromethoxy,trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy,propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, perfluorobutoxy,pentyloxy, hexyloxy, octyloxy and decyloxy groups, etc.), anoptionally-halogenated C₁₋₄ alkylthio group (e.g., methylthio,difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,isopropylthio and butylthio groups, etc.), an amino group, a mono- ordi-C₁₋₄ alkylamino group (e.g., methylamino, ethylamino, propylamino,dimethylamino and diethylamino groups, etc.), a cyclic amino group(e.g., a 5-membered to 9-membered cyclic amino group optionally havingfrom 1 to 3 hetero atoms such as oxygen and sulfur atoms, etc., inaddition to nitrogen atoms, concretely for example, pyrrolidino,piperidino and morpholino groups, etc.), a C₁₋₄ alkyl-carbonylaminogroup (e.g., acetylamino, propionylamino and butyrylamino groups, etc.),an aminocarbonyloxy group, a mono- or di-C₁₋₄ alkylaminocarbonyloxygroup (e.g., methylaminocarbonyloxy, ethylaminocarbonyloxy,dimethylaminocarbonyloxy and diethylaminocarbonyloxy groups, etc.), aC₁₋₄ alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino and propylsulfonylamino groups, etc.), a C₁₋₄alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl groups, etc.), anaralkyloxycarbonyl group (e.g., benzyloxycarbonyl group, etc.), acarboxyl group, a C₁₋₆ alkyl-carbonyl group (e.g., methylcarbonyl,ethylcarbonyl and butylcarbonyl groups, etc.), a C₃₋₆cycloalkyl-carbonyl group (e.g., cyclohexylcarbonyl group, etc.), acarbamoyl group, a mono- or di-C₁₋₄ alkylcarbamoyl group (e.g.,methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl,diethylcarbamoyl and dibutylcarbamoyl groups, etc.), a C₁₋₆alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl andpropylsulfonyl groups, etc.), etc.

The homocyclic Ring C may optionally be substituted, for example, by one5-membered or 6-membered, aromatic monocyclic heterocyclic group (e.g.,furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl groups,etc.), etc., and the aromatic monocyclic heterocyclic group mayoptionally be substituted by from 1 to 3 or so optionally halogenatedC₁₋₄ alkyl groups (e.g., methyl, chloromethyl, difluoromethyl,trichloromethyl, trifluoromethyl, ethyl and isopropyl groups, etc.),etc.

As preferred substituents for the homocyclic Ring C (e.g., benzene ring,etc.), for example, mentioned are a halogen atom (e.g., fluorine,chlorine and bromine atoms, etc.), an optionally halogenated C₁₋₆ alkylgroup (e.g., methyl, chloromethyl, difluoromethyl, trichloromethyl,trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,perfluoroethyl, propyl, isopropyl, 3,3,3-trifluoropropyl, butyl,s-butyl, t-butyl and perfluorobutyl groups, etc.), a nitro group, ahydroxyl group, an optionally halogenated C₁₋₆ alkoxy group (e.g.,methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy,3,3,3-trifluoropropoxy and butoxy groups, etc.), an amino group, a mono-or di-C₁₋₄ alkylamino-substituted C₁₋₄ alkyl group (e.g.,methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl and2-dimethylaminoethyl groups, etc.), a mono- or di-C₁₋₄ alklamino group(e.g., methylamino, ethylamino, dimethylamino and diethylamino groups,etc.), a C₁₋₄ alkoxy-carbonyl group (e.g., methoxycarbonyl andethoxycarbonyl groups, etc.), a carboxyl group, a carbamoyl group, etc.

More preferred are a halogen atom (e.g., fluorine, chlorine and bromineatoms, etc.), an optionally halogenated C₁₋₄ alkyl group (e.g., methyl,chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,2-bromoethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl,perfluoroethyl, propyl, isopropyl and t-butyl groups, etc.), anoptionally halogenated C₁₋₄ alkoxy group (e.g., methoxy,trifluoromethoxy, ethoxy, 2,2,2-trichloroethoxy, 2,2,2-trifluoroethoxy,perfluoroethoxy and propoxy groups, etc.), a di-C₁₋₄ alkylamino group(e.g., dimethylamino and diethylamino groups, etc.), a C₁₋₃ acyloxygroup (e.g., acetoxy group, etc.), a hydroxyl group, etc. Preferably,the number of the substituents is, for example, from 1 to 3 or so.

Especially, preferred are a halogen atom (e.g., fluorine, chlorine andbromine atoms, etc.), an optionally halogenated C₁₋₄ alkyl group (e.g.,methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl,perfluoroethyl, propyl, isopropyl and t-butyl groups, etc.), anoptionally halogenated C₁₋₄ alkoxy group (e.g., methoxy,trifluoromethoxy, ethoxy, 2,2,2-trichloroethoxy, 2,2,2-trifluoroethoxy,perfluoroethoxy and propoxy groups, etc.)

The "heterocyclic ring" of the "optionally substituted heterocyclicring" includes, for example, from 5-membered to 10-membered heterocyclicrings having from 1 to 4 hetero atoms of the same type or different twotypes, such as nitrogen, oxygen and/or sulfur atoms, etc., in additionto carbon atoms, etc. Concretely, the heterocyclic ring includes, forexample;

(1) 5-membered or 6-membered, aromatic monocyclic heterocyclic rings,such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, etc.;

(2) 9-membered or 10-membered, aromatic, condensed heterocyclic rings,such as benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indoliyl,isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl,1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl,carbazolyl, a-carbolinyl, β-carbolinyl, g-carbolinyl, acridinyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolizinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.;

(3) from 5-membered to 10-membered, non-aromatic heterocyclic rings,such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuryl, piperidyl, tetrahydrofuranyl, morpholinyl,thiomorpholinyl, pyrazinyl, etc.

Of the above-mentioned heterocyclic rings (1) to (3), for example,5-membered or 6-membered heterocyclic rings having from 1 to 3 heteroatoms, such as nitrogen, oxygen and sulfur atoms, etc., in addition tocarbon atoms, are widely utilized. Such heterocyclic rings include, forexample, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl,pyrazolyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, thiazolyl,thiadiazolyl, thiophenyl, etc.

As the substituents for the optionally substituted heterocyclic rings,mentioned are substituents such as those as referred to hereinabove forthe foregoing "optionally substituted homocyclic rings".

More preferably, Ring C includes optionally substituted benzene rings(especially, substituted benzene rings), for example, benzene ringsoptionally substituted by from 1 to 3 substituents selected from ahalogen atom, an optionally halogenated C₁₋₄ alkyl group, an optionallysubstituted C₁₋₄ alkoxy group, a di-C₁₋₄ alkylamino group, a C₁₋₃acyloxy group and a hydroxyl group (especially, benzene ringssubstituted by such substituent(s)). Concretely, the preferred Ring Cincludes, for example, optionally substituted benzene rings of a formula(C-1): ##STR41## wherein C¹, C² and C³ are the same or different andrepresent, independently, a hydrogen atom, a halogen atom, an optionallyhalogenated C₁₋₄ alkyl group, an optionally halogenated C₁₋₄ alkoxygroup, a mono- or di-C₁₋₄ alkylamino group, a C₁₋₃ acyloxy group or ahydroxyl group; and optionally substituted benzene rings of a formula(C-2): ##STR42## wherein C⁴ and C⁵ are the same or different andrepresent, independently, a hydrogen atom, a halogen atom, an optionallyhalogenated C₁₋₄ alkyl group or an optionally halogenated C₁₋₄ alkoxygroup.

The halogen atom, the optionally halogenated C₁₋₄ alkyl group, theoptionally halogenated C₁₋₄ alkoxy group and the mono- or di-C₁₋₄alkylamino group to be represented by any of C¹, C², C³, C⁴ and C⁵ maybe the same as the above-mentioned halogen atom, optionally halogenatedC₁₋₄ alkyl group, optionally halogenated C₁₋₄ alkoxy group and mono- ordi-C₁₋₄ alkylamino group, respectively.

Even more preferably, Ring C includes, for example, benzene rings of theabove-mentioned formulae (C-1) and (C-2) where C¹ to C⁵ are as follows:

(1) C¹, C² and C³ are the same or different and represent,independently, a halogen atom, an optionally halogenated C₁₋₄ alkylgroup or an optionally halogenated C₁₋₄ alkoxy group;

(2) C¹, C² and C³ are the same or different and represent,independently, a halogen atom or an optionally halogenated C₁₋₄ alkylgroup;

(3) C¹, C² and C³ are the same or different and represent,independently, a halogen atom;

(4) C¹, C² and C³ are the same or different and represent,independently, an optionally halogenated C₁₋₄ alkyl group;

(5) C¹, C² and C³ are the same or different and represent,independently, an optionally halogenated C₁₋₄ alkoxy group;

(6) C⁴ and C⁵ are the same or different and represent, independently, ahalogen atom;

(7) C⁴ and C⁵ are the same or different and represent, independently, anoptionally halogenated C₁₋₄ alkyl group; or (8) C⁴ and C⁵ are the sameor different and represent, independently, an optionally halogenatedC₁₋₄ alkoxy group.

As examples of the "optionally halogenated C₁₋₄ alkyl group", the"optionally halogenated C₁₋₄ alkoxy group" and the "halogen atom" in theabove-mentioned embodiments (1) to (8), referred to are the same ones asthose mentioned hereinabove.

Further more preferably, Ring C includes, for example, benzene rings ofthe above-mentioned formula (C-2) where C⁴ and C⁵ are as follows:

(a) one of C⁴ and C⁵ is a hydrogen atom and the other is a methoxygroup;

(b) C⁴ and C⁵ are both chlorine atoms;

(c) one of C⁴ and C⁵ is a methoxy group and the other is an isopropylgroup;

(d) one of C⁴ and C⁵ is a methoxy group and the other is a1-methoxy-1-methylethyl group; or

(e) C⁴ and C⁵ are both trifluoromethyl groups.

Regarding "Ring Z"

In the above-mentioned formulae, Ring Z represents anoptionally-substituted nitrogen containing heterocyclic ring. Varioussubstituents are referred to as substituents for Ring Z, which include,for example, an alkyl group (e.g., a linear or branched alkyl grouphaving from 1 to 6 carbon atoms, preferably a linear or branched alkylgroup having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups, etc.), analkenyl group (e.g., an alkenyl group having from 2 to 6 carbon atoms,preferably an alkenyl group having from 2 to 4 carbon atoms, such asethenyl, propenyl, isopropenyl, butenyl, isobutenyl sec-butenyl groups,etc.), an alkynyl group (e.g., an alkynyl group having from 2 to 6carbon atoms, preferably an alkynyl group having from 2 to 4 carbonatoms, such as ethynyl, propynyl, isopropynyl, butynyl, isobutynyl andsec-butynyl groups, etc.), a cycloalkyl group (e.g., a C₃₋₈ cycloalkylgroup, preferably a C₃₋₆ cycloalkyl group, such as cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl groups, etc.), a cycloalkyl-alkylgroup (e.g., a C₃₋₆ cycloalkyl-C₁₋₄ alkyl group, such ascyclopropylmethyl, cyclopropylethyl and cyclohexylmethyl groups, etc.),an aryl group (e.g., an aryl group having from 6 to 14 carbon atoms,preferably an aryl group having from 6 to 10 carbon atoms, such asphenyl, 1-naphthyl, 2-naphthyl, anthryl and phenanthryl groups, etc.,especially, phenyl group), a nitro group, a cyano group, a hydroxylgroup, a C₁₋₄ alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxyand butoxy groups, etc.), a C₁₋₄ alkylthio group (e.g., methylthio,ethylthio and propylthio groups, etc.), an amino group, a mono- ordi-C₁₋₄ alkylamino group (e.g., methylamino, ethylamino, propylamino,dimethylamino and diethylamino groups, etc.), a cyclic amino group(e.g., a 5-membered to 9-membered cyclic amino group optionally havingfrom 1 to 3 hetero atoms, such as oxygen and sulfur atoms, etc., inaddition to nitrogen atom, concretely, for example, pyrrolidino,piperidino, morpholino and thiomorpholino groups, etc.), a C₁₋₄alkyl-carbonylamino group (e.g., acetylamino, propionylamino andbutyrylamino groups, etc.), a C₁₋₄ alkylsulfonylamino group (e.g.,methylsulfonylamino and ethylsulfonylamino groups, etc.), a C₁₋₄alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl andpropoxycarbonyl groups, etc.), a carboxyl group, a C₁₋₆ alkyl-carbonylgroup (e.g., methylcarbonyl, ethylcarbonyl and propylcarbonyl groups,etc.), a carbamoyl group, a mono- or-di-C₁₋₄ alkylcarbamoyl group (e.g.,methylcarbamoyl and ethylcarbamoyl groups, etc.), a C₁₋₆ alkylsulfonylgroup (e.g., methylsulfonyl, ethylsulfonyl and propylsulfonyl groups,etc.), an oxo group, a thioxo group, etc. The number of the substituentsis, for example, from 1 to 5 or so, preferably 1, 2 or so, depending onthe size of Ring Z.

Ring Z may be a heterocyclic ring optionally having at least one heteroatom selected from nitrogen, oxygen and sulfur atoms, in addition to Yand the nitrogen atom N, and is preferably an optionally oxoated ring.

Ring Z includes rings of a formula (Z-1): ##STR43## wherein D and Erepresent groups from which Ring Z as mentioned above is formed via thenitrogen atom adjacent to E.

Preferably, D and E which form Ring Z represent, independently, analkylene group optionally having an oxo group, oxyalkylene group, oriminoalkylene group. The alkylene groups optionally having an oxo groupto be represented by D and E preferably have carbon atoms from whichRing Z is formed to be a 5-membered to 12-membered ring, preferably a5-membered to 9-membered ring. The numbers of the carbon atoms thatconstitute the alkylene groups of D and E may be the same or different.

Preferably, D includes, for example, C₁₋₇ alkylene group optionallyhaving an oxo group, especially C₁₋₅ alkylene group optionally having anoxo group C₁₋₇ oxyalkylene groups, especially C₁₋₅ oxyalkylene groups,C₁₋₇ iminoalkylene groups, especially C₁₋₅ imminoalkylene groups. Morepreferably, D includes an alkylene group of a formula --(CH₂)_(m) --(where m is from 1 to 7), an oxyalkylene group of a formula--O--(CH₂)_(p) (where p is from 1 to 7), iminoalkylene group of aformula --NH--(CH₂)_(q) (where q is from 1 to 7. In these formula, m ispreferably from 1 to 5, more preferably from 2 to 5.

Preferably, E includes, for example, C₁₋₃ alkylene group optionallyhaving an oxo group, more preferably an alkylene group optionally havingan oxo group having one or two carbon atoms, even more preferably amethylene group optionally having an oxo group.

The number of the oxo groups that are substitutable in Ring Z is notspecifically limited but may be selected from 1 to 3 or so depending onthe size of Ring Z. Where Ring Z is a 5-membered to 10-membered ring,the number of the substitutable oxo groups is 1, 2 or so. Oxo group(s)may be substituted at at least either one of D and/or E. Preferably, oxogroup(s) is/are substituted at E in Ring Z.

Preferably, in Ring Z, D is an alkylene group or oxyalkylene grouphaving from 1 to 5 carbon atoms, more preferably from 2 to 5 carbonatoms especially, an alkylene group having from 2 to 5 carbon atoms,while E is an alkylene group having an oxo group having 1 or 2 carbonatoms, especially >C═O. Especially preferably, Ring Z includes, forexample, from 5-membered to 9-membered rings of a formula (Z-2):##STR44## wherein each m and p, independently, represents an integer offrom 1 to 5. Regarding "n"

In the above-mentioned formulae, n represents an integer of from 1 to 6,preferably an integer of from 1 to 3, especially preferably 1 or 2. Morepreferably, n is 1.

Regarding Compounds (I) and (Ia)

In compounds of the above-mentioned general formulae (I) and (Ia), thecombination of "Ring M" "--X . . . . . Y<", "R^(a) ", "R^(b) ", "RingA", "Ring B", "Ring C", "Ring Z" and "n" is not specifically limited.These may be combined suitably to construct the compounds (I) and (Ia).Preferred compounds (I) and (Ia) are constructed by combining theabove-mentioned preferred embodiments of "Ring M" "--X . . . . . Y<","R^(a) ", "R^(b) ", "Ring A", "Ring B", "Ring C", "Ring Z" and "n".

Of compounds of the above-mentioned general formula (I), especiallythose of the above-mentioned general formula (Ia), preferred are (1) thefollowing compounds or pharmaceutically-acceptable salts thereof.

Compounds of formula (I) or (Ia) wherein;

one of Ring A and Ring B is a 5-membered or 6-membered heterocyclic ringhaving one or two hetero atoms selected from nitrogen and oxygen atoms,in addition to carbon atoms, while the other is a benzene ring, and theRings A and B may optionally have one or two substituents selected froma halogen atom and an optionally halogenated C₁₋₄ alkyl group;

Ring C is a benzene ring optionally having from 1 to 3 substituentsselected from a halogen atom, an optionally halogenated C₁₋₆ alkyl group(preferably, C₁₋₄ alkyl group) and an optionally halogenated C₁₋₆ alkoxygroup (preferably, C₁₋₄ alkoxy group);

D that constitutes Ring Z is --(CH₂)_(m) -- (where m is an integer offrom 1 to 7) or --O--(CH₂)p-- (where p is an integer of from 1 to 7);

E that constitutes Ring Z is >C=O;

--X . . . . . Y< is --CO--N<;

n is 1,

or pharmaceutically-acceptable salts thereof.

The above-mentioned "5-membered or 6-membered heterocyclic ring"includes, for example, pyridine, pyrazine, pyrrole, thiophene, thiazole,tetrahydropyrazine, piperidine, etc. Concretely, Ring A includesheterocyclic rings of the above-mentioned formula (A-5), etc., and RingB includes benzene rings of the above-mentioned formulae (B-7) and(B-8), especially the above-mentioned formula (B-10), etc.

The above-mentioned "halogen atom" includes, for example, fluorine,chlorine and bromine atoms, etc.; the "optionally-halogenated C₁₋₄ alkylgroup" includes, for example, methyl, chloromethyl, difluoromethyl,trichloromethyl, trifluoromethyl, ethyl; 2-bromoethyl,2,2,2-trifluoroethyl, perfluoroethyl, propyl, 3,3,3-trifluoropropyl,isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl,isobutyl, sec-butyl and tert-butyl groups, etc.; the "optionallyhalogenated C₁₋₆ alkyl group" includes pentyl and hexyl groups, etc., inaddition to the above-mentioned alkyl groups and halogenated alkylgroups.

The "optionally halogenated C₁₋₄ alkoxy group" includes, for example,methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy and tert-butoxy groups,etc.; and the "optionally halogenated C₁₋₆ alkoxy group" includespentyloxy and hexyloxy groups, etc., in addition to the above-mentionedalkoxy groups and halogenated alkoxy groups.

Of compounds of the above-mentioned general formula (I), especiallythose of the above-mentioned general formula (Ia), also preferred are(2) the following compounds or pharmaceutically-acceptable saltsthereof.

Compounds of formula (I) or (Ia) wherein:

Ring A is a 5-membered or 6-membered heterocyclic ring having onenitrogen atom or one sulfur atom, in addition to carbon atoms, forexample, a heterocyclic ring of a formula (A-7): ##STR45## Ring B is abenzene ring optionally having from 1 to 3 substituents selected from ahalogen atom and an optionally halogenated C₁₋₄ alkyl group;

Ring C is a benzene ring optionally having from 1 to 3 substituentsselected from a halogen atom, an optionally halogenated C₁₋₄ alkyl groupand an optionally halogenated C₁₋₄ alkoxy group;

D that constitutes Ring Z is --(CH₂)_(m) -- (where m is an integer offrom 1 to 7) or --O--(CH₂)p-- (where p is integer of from 1 to 7);

E that constitutes Ring Z is >C═O;

--X . . . . . Y< is --CO--N<;

n is 1,

or pharmaceutically-acceptable salts thereof.

As examples of the "halogen atom", the "optionally halogenated C₁₋₄alkyl group" and the "optionally halogenated C₁₋₄ alkoxy group",mentioned are those as referred to hereinabove for the foregoingcompounds (1).

More preferably, compounds of formula (I) or (Ia) wherein;

R^(a) and R^(b) are the same or different and represent, independently,a hydrogen atom, optionally halogenated C₁₋₄ alkyl groups, C₁₋₆alkoxy-C₁₋₆ alkyl groups, C₁₋₆ alkylthio-C₁₋₆ alkyl groups, amino-C₁₋₆alkyl groups, C₁₋₇ acylamino-C₁₋₆ alkyl groups, mono- or di-C₁₋₆alkylamino-C₁₋₄ alkyl groups, C₃₋₁₀ cycloalkylamino-C₁₋₆ alkyl groups,C₁₋₆ alkyl groups having 5-membered or 6-membered cyclioamino whichoptionally substituted by C₁₋₆ alkyl, C₁₋₆ alkylsulfonylamino-C₁₋₆ alkylor C₁₋₆ alkylcarbonyloxy-C₁₋₆ alkyl; or

R^(a) and R^(b) are bonded to each other to form pyridine ring which isoptionally substituted by 1 to 3 substituents selected from a halogenatom and a C₁₋₄ alkyl group;

Ring B is a benzene ring optionally having 1 to 3 substituents selectedfrom a halogen atom, an optionally halogenated C₁₋₄ alkyl group and anoptionally halogenated C₁₋₄ alkoxy group;

Ring C is a benzene ring optionally having 1 to 3 substituents selectedfrom a halogen atom, an optionally halogenated C₁₋₄ alkyl group, anoptionally halogenated C₁₋₄ alkoxy group, an amino group optionallysubstituted by C₁₋₄ alkyl group, a C₁₋₃ acyloxy group and a hydroxylgroup;

Ring Z is a 5-membered to 10-membered nitrogen containing heterocyclicring optionally having an oxo group and optionally substituted C₁₋₄alkyl group or a hydroxy group;

--X . . . . . Y-- is --N═CC< or --CO--N< and n is an integer of 1;

and n is 1, or pharmaceutically-acceptable salts thereof.

Preferred compounds of formulae (I) and (Ia) include, for example,compounds of the following general formula or salts thereof. ##STR46##wherein D and E represent alkylene groups, optionally having an oxogroup and the other symbols have the same meanings as above.

Preferably, D and E represent, independently, a C₁₋₃ alkylene groupoptionally substituted by one oxo group.

More preferred compounds of formulae (I) and (Ia) include, for example,compounds of the following general formula or salts thereof. ##STR47##wherein m represents an integer of from 1 to 7, and the other symbolshave the same meanings as above.

m is preferably an integer of from 2 to 5.

Where the above-mentioned compounds of formulae (I) and (Ia) form saltsand used in medicines, it is preferable that the salts arepharmaceutically-acceptable salts.

Examples of such pharmaceutically-acceptable salts include salts withinorganic acids, such as hydrochloric acid, sulfuric acid, phosphoricacid, diphosphoric acid, hydrobromic acid, nitric acid, etc., or saltswith organic acids, such as acetic acid, malic acid, maleic acid,fumaric acid, tartaric acid, succinic acid, citric acid, lactic acid,methanesulfonic acid, p-toluenesulfonic acid, palmitic acid, salicylicacid, stearic acid, etc.

Compounds (I) and (Ia) or salts thereof of the present invention includestereoisomers such as cis- and trans-isomers, etc., racemates, as wellas optically-active forms such as R-forms, S-forms, etc. Depending onthe size of Ring Z, compounds (I) and (Ia) or salts thereof may includeconformation-dependent isomers. All such isomers are within the scope ofthe compounds (I) and (Ia) or salts thereof of the present invention.

Method for Producing Compounds or Salts Thereof

Compounds (I) and (Ia) or salts thereof of the present invention can beproduced, for example, by cyclizing a compound of the following generalformula (II) or a salt thereof. ##STR48## wherein L represents a leavinggroup, and the other symbols have the same meanings as above.

The leaving group L in compound (II) includes, for example, a halogenatom (e.g., chlorine, bromine and iodine atoms, etc.), a substitutedsulfonyloxy group (e.g., methanesulfonyloxy, ethanesulfonyloxy,benzenesulfonyloxy and p-toluenesulfonyloxy groups, etc.), etc.

The compound (II) can be applied to the reaction as a free compound butmay also be applied thereto as its salt (for example, as an alkali metalsalt, such as lithium, sodium, potassium or the like salt, of thecompound). In general, the reaction is conducted in a solvent that isinert to the reaction. As the solvent, for example, preferably used isany of halogenated hydrocarbons such as dichloromethane, chloroform,etc., nitriles such as acetonitrile, etc., ethers such asdimethoxyethane, tetrahydrofuran, etc., aprotic polar solvents such asdimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc.

Addition of a base to the reaction system advantageously promotes thereaction. As the base, for example, advantageously employed is any ofinorganic bases (alkali metal hydroxides such as sodium hydroxide,potassium hydroxide, etc.; alkali metal hydrogencarbonates such assodium hydrogencarbonate, potassium hydrogencarbonate, etc.; alkalimetal carbonates such as sodium carbonate, potassium carbonate, etc.;alkali metal hydrides such as sodium hydride, potassium hydride, etc.;sodium amide; alkoxides such as sodium methoxide, sodium ethoxide,etc.), and organic bases (amines such as trimethylamine, triethylamine,diisopropylethylamine, etc.; cyclic amines such as pyridine, etc.).

In the above-mentioned cyclization, it is also possible to convert thecompound (II) into its salt with a base (for example, any of theabove-mentioned alkali metal salts, alkaline earth metal salts, etc.)prior to the reaction, in place of using the base. The amount of thebase, if used, varies, depending on the kind of the compound (II) andthe solvent to be used and on the other reaction conditions, and is, ingeneral, from 1 to 10 mols or so, preferably from 1 to 5 mols or so, permol of the compound (II) used.

The reaction temperature falls, for example, within the range betweenabout -50° C. and about 200° C., preferably between about -20° C. andabout 150° C. The reaction time varies, depending on the kind of thecompound (II) used or the kind of its salt used and also on the reactiontemperature, etc., and is, for example, from 1 to 72 hours or so,preferably from 1 to 24 hours or so.

Of compounds (I) and (Ia) of the present invention, those where Ring Ais a tetrahydropyridine ring can be produced by reducing compounds (I)and (Ia) where Ring A is a pyridine ring. The reduction can be conductedby various methods. For example, preferred is a method of reducing thecompounds in the presence of a metal catalyst for catalytic reduction.The catalyst to be employed in the catalytic reduction includes, forexample, platinum catalysts such as platinum black, platinum oxide,platinum carbon, etc., palladium catalysts such as palladium black,palladium oxide, palladium barium sulfate, palladium carbon, etc.;nickel catalysts such as reduced nickel, nickel oxide, Raney nickel,Urushibara nickel, etc. The amount of the catalyst to be used varies,depending on the type of the catalyst, and is, in general, from 0.1 to10% (w/w) or so relative to the compound (I) or (Ia) to be reduced.

The reduction is generally conducted in a solvent. The solvent includes,for example, alcohols such as methanol, ethanol, propanol, isopropanol,etc., ethers such as tetrahydrofuran, dioxane, etc., esters such asethyl acetate, etc. The reaction temperature falls, for example, between0° C. and 200° C. or so, preferably between 20° C. and 110° C. or so.The reaction time is generally from 0.5 to 48 hours or so, preferablyfrom 1 to 16 hours or so. In general, the reaction is conducted undernormal pressure in many cases but, if desired, may be conducted underpressure (for example, at from 3 to 10 atmospheres or so).

The reduction may also apply to the conversion of other aromaticheterocyclic rings into non-aromatic heterocyclic rings.

Compounds of formulae (I) and (Ia) where Ring A is a tetrahydropyridinering can also be produced by reacting a compound of formula (I) or (Ia)where Ring A is a pyridine ring with an alkylating agent of a formula,Q-L' (where Q represents an optionally substituted alkyl group, and L'represents a removable group) to convert it into the correspondingquaternary salt, followed by reducing the resulting quaternary salt. Asexamples of the removable group L', referred to are those of theremovable group L as mentioned hereinabove.

The alkylating agent Q-L' that is used for converting the compound intothe corresponding quaternary salt includes alkane halides (e.g.,chlorides, bromides, iodides, etc.), sulfates and sulfonates (e.g.,methanesulfonates, p-toluenesulfonates, benzenesulfonates, etc.), etc.Especially preferred are alkyl halides. The amount of the alkylatingagent to be used is, for example, from 1 to 100 equivalents or so,preferably from 1 to 30 equivalents or so, per mol of the substrate.

The alkylation is generally conducted in a solvent. The solventincludes, for example, alcohols such as methanol, ethanol, propanol,isopropanol, etc., ethers such as tetrahydrofuran, dioxane, etc., esterssuch as ethyl acetate, etc., halogenated hydrocarbons such asdichloromethane, 1,2-dichloroethane, etc. It is also possible to use thealkylating agent itself as the solvent. The reaction temperature falls,for example, between 10° C. and 200° C. or so, preferably between 20° C.and 110° C. or so. The reaction time is generally from 0.5 to 24 hoursor so, preferably from 1 to 16 hours or so.

The reduction of the quaternary salt as formed in the previous reactioninto a tetrahydropyridine ring may be conducted in the presence of areducing agent, such as a metal hydride or the like, in an inertsolvent. The metal hydride to be used as the reducing agent includes,for example, sodium borohydride, lithium borohydride, zinc borohydride,sodium borocyanohydride, lithium borocyanohydride, lithium aluminiumhydride, etc. Of these, preferred are sodium borohydride, etc. Theamount of the reducing agent to be used is, for example, from 1 to 10equivalents or so, preferably from 1 to 2 equivalents or so, relative tothe quaternary salt. The reaction solvent includes, for example, loweralcohols such as methanol, ethanol, etc., ethers such as dioxane,tetrahydrofuran, etc., hydrocarbons such as benzene, toluene, etc. Thesesolvents can be used singly or as combined. The reaction temperaturefalls, in general, between about -100° C. and about 40° C., preferablybetween about -80° C. and about 25° C. The reaction time is generallyfrom 5 minutes to 10 hours or so, preferably from 10 minutes to 5 hoursor so.

As the case may be, the reduction of the above-mentioned quaternarysalts may give compounds of the present invention having adihydropyridine ring, depending on the type of the quaternary salts tobe reduced. The dihydropyridine ring thus formed may further be reducedinto a tetrahydropyridine ring, for example, according to theabove-mentioned catalytic reduction or the like. Where Ring A is atetrahydropyridine ring and its nitrogen atom has a hydrogen atom asbonded thereto, it may be alkylated with the above-mentioned alkylatingagent of formula Q-L' (where the symbols have the same meanings asabove) to thereby introduce the group Q into the nitrogen atom of thering. In this manner, therefore, compounds of the invention where thenitrogen atom of the tetrahydropyridine Ring A is substituted by thegroup Q are obtained.

It is also possible to obtain compounds of the invention where Ring A isa pyridone ring by oxidizing the corresponding compounds where Ring A isa quaternary salt of a pyridine ring. The oxidation can be conducted,for example, in accordance with a known method (see E. A. Prill et al.;Organic Syntheses, Combined Vol. 2. p. 419 (1957)) or with referencethereto.

Compounds of the invention where Ring B is an aromatic heterocyclic ringcan be converted into the corresponding compounds where Ring B is anon-aromatic heterocyclic ring by reducing them in the same manner asabove.

Of compounds (I) of the present invention, those where --X . . . . . Y<is --CS--N< can be produced by reacting the corresponding compoundswhere --X . . . . . Y< is --CO--N< with a suitable sulfide. The sulfideincludes, for example, phosphorus pentasulfide, Lowesson reagents, etc.This reaction is, in general, conducted in the absence of water in asolvent, for example in a halogenated hydrocarbon such asdichloromethane, chloroform or the like, an ether such as dioxane,tetrahydrofuran or the like, or a hydrocarbon such as benzene, tolueneor the like. The amount of the sulfide to be used is not smaller thanthe equimolar amount, preferably from 2 to 5 mols or so, relative to thecompound to be sulfidized therewith. The reaction temperature falls, forexample, between 20° C. and 120° C or so. The reaction time varies,depending on the kind of the compound to be sulfidized, the type of thesulfide to be used, the reaction temperature, etc., and is, for example,from 1 to 8 hours or so.

Where the compounds (I) and (Ia) or salts thereof which are producedaccording to the methods mentioned above have lower (C₁₋₆) alkoxygroup(s) at the benzene ring(s) in the groups of Ring A, Ring B and RingC, if desired, these may optionally be reacted with, for example, borontribromide or the like according to known methods to thereby convert thelower alkoxy group(s) into hydroxyl group(s). This reaction may beconducted, in general, in a solvent (e.g., halogenated hydrocarbons suchas dichloromethane, chloroform, carbon tetrachloride, etc., hydrocarbonssuch as benzene, toluene, etc.), at from about -20° C. to about 80° C.,preferably at from about 0° C. to about 30° C. The amount of borontribromide to be used is from about 1 to about 10 molar equivalents,preferably from about 1 to about 5 molar equivalents, relative to onelower alkoxy group. The reaction time is, in general, from 15 minutes to24 hours or so, preferably from 30 minutes to 12 hours or so.

Where the compounds (I) and (Ia) or salts thereof which are producedaccording to the methods mentioned above have hydroxyl group(s) at thebenzene ring(s) in the groups of Ring A, Ring B and ring C, if desired,these may be alkylated or acylated to thereby convert the hydroxylgroup(s) into alkoxy or acyloxy group(s).

The alkylation may be conducted in the presence of a base in a solventby making the compounds reacted with an alkylating agent. The solventincludes, for example, alcohols such as methanol, ethanol, propanol,etc., ethers such as dimethoxyethane, dioxane, tetrahydrofuran, etc.,ketones such as acetone, etc., amides such as N,N-dimethylformamide,etc. The base includes, for example, organic bases such astrimethylamine, triethylamine, N-methylmorpholine, pyridine, picoline,N,N-dimethylaniline, etc., and inorganic bases such as potassiumcarbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, etc.

The alkylating agent includes, for example, optionally substitutedalkane halides (e.g., chlorides, bromides, iodides, etc.), sulfates andsulfonates (e.g., methanesulfonates, p-toluenesulfonates,benzenesulfonates, etc.), etc. The amount of the alkylating agent to beused is from about 1 to about 5 molar equivalents, preferably from about1 to about 3 molar equivalents, relative to mol of the starting phenolicderivative. The reaction temperature falls, in general, between about-10° C. and about 100° C., preferably from about 0° C. and about 80° C.The reaction time is, in general, from 15 minutes to 24 hours or so,preferably from 30 minutes to 12 hours or so.

The acylation is conducted by reacting the phenolic derivative with adesired carboxylic acid or a reactive derivative thereof. This reactionis generally conducted in a solvent, though depending on the type of theacylating agent to be used and the kind of the starting phenolicderivative to be acylated. If desired, a base may be added to thereaction system so as to promote the reaction. The solvent includes, forexample, hydrocarbons such as benzene, toluene, etc., ethers such asethyl ether, dioxane, tetrahydrofuran, etc., esters such as ethylacetate, etc., halogenated hydrocarbons such as chloroform,dichloromethane, etc., amides such as N,N-dimethylformamide, etc.,aromatic amines such as pyridine, etc. The base includes, for example,hydrogencarbonates such as sodium hydrogencarbonate, potassiumhydrogencarbonate, etc., carbonates such as sodium carbonate, potassiumcarbonate, etc., acetates such as sodium acetate, etc., tertiary aminessuch as triethylamine, etc., aromatic amines such as pyridine, etc. Thereactive derivative of a carboxylic acid, which is used as the acylatingagent, includes, for example, acid anhydrides, mixed acid anhydrides,acid halides (e.g., chlorides, bromides), etc. The amount of theacylating agent to be used is from 1 to 5 molar equivalents, preferablyfrom 1 to 3 molar equivalents, relative to mol of the starting phenolicderivative. The reaction temperature falls, in general, between 0° C.and 150° C. or so, preferably about 10° C. and 100° C. or so. Thereaction time is generally from 15 minutes to 12 hours or so, preferablyfrom 30 minutes to 6 hours or so.

Of compounds of formula (I) and (Ia), those where D is a carbonyl group,an oxyalkylene group [--O--(CH₂)_(q) --] or an iminoalkylene group[--NH--(CH₂)_(q) --] can be obtained by reacting the leaving group La(for example, the above-mentioned removable group L such as a halogenatom or the like, an amido group optionally having a substituent at itsnitrogen atom, etc.) as substituted on the Ring M in the absence of Dwith the reactive moiety (for example, the active hydrogen atom of ahydroxyl group, an amino group, a mono-C₁₋₆ alkylamino group or thelike) of the substituent as bonded to the nitrogen atom adjacent to E,in accordance with the methods mentioned above. The substituent asbonded to the nitrogen atom adjacent to E is, for example, a linear orbranched C₁₋₆ alkylene group optionally having substituent(s) selectedfrom a C₁₋₆ alkyl group, a hydroxyl group, a C₁₋₆ alkoxy group, etc.

Where the compounds (I) and (Ia) are obtained in the above-mentionedmethods as free compounds, they can be converted into their salts byordinary methods, for example, into their salts with inorganic acids(e.g., hydrochloric acid, sulfuric acid, hydrobromic acid, etc.),organic acids (e.g., methanesulfonic acid, benzenesulfonic acid,toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, tartaricacid, etc.), inorganic bases (e.g., alkali metals such as sodium,potassium, etc., alkaline earth metals such as calcium, magnesium, etc.,aluminium, ammonium, etc.), organic bases (e.g., trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc.),etc. Where the compounds (I) are obtained in the form of their salts,the salts may be converted into free compounds or other salts byordinary methods.

The final compounds (I) and (Ia) or salts thereof thus producedaccording to the methods mentioned hereinabove can be separated andisolated by ordinary separation and isolation means (for example, bycondensation, solvent extraction, column chromatography,recrystallization, etc.). Where the compounds (I) and (Ia) are ofoptically-active forms, they can be resolved into d-forms and 1-forms byconventional optical resolution.

Of the starting compounds (II) that are used for producing the compounds(I) and (Ia) or salts thereof of the present invention, compounds (IIa)wherein --X . . . . . Y< is --CO--N<, D is an ethylene group, and Eis >C═O can be produced, for example, according to the followingreaction process (1): ##STR49##

In these formulae, the symbols have the same meanings as above.

The step (1) and the step (2) in the above-mentioned reaction process(1) can be conducted in accordance with known methods for producing thecorresponding isoquinolone-skeleton compounds where Ring A and Ring Bare both optionally substituted benzene rings (for example, a methoddescribed in EP-A-481383, etc.). The step (1) is to produce an amidecompound (IV) by reacting the carboxyl group in a compound (III) and theamino group in an iminodiacetonitrile. This reaction may be conducted,in general, in a solvent, by using a compound (III) or acarboxyl-reactive derivative thereof and an iminodiacetonitrile. Thereactive derivative includes, for example, acid halides, mixed acidanhydrides, active esters, etc. The solvent includes, for example,halogenated hydrocarbons such as chloroform, dichloromethane,1,2-dichlroethane, etc., ethers such as ethyl ether, tetrahydrofuran,dioxane, dimethoxyethane, etc., esters such as ethyl acetate, etc.,hydrocarbons such as benzene, toluene, etc., pyridine, amides such asN,N-dimethylformamide, etc. The amount of the iminodiacetonitrile isfrom 1 to 5 molar equivalents or so, preferably from 1 to 3 molarequivalents or so, relative tool of the reactive derivative of theabove-mentioned compound (III).

The reaction may be conducted in the presence of a base, by which thereaction is promoted. The base includes, for example, organic bases(e.g., alkylamines such as triethylamine, etc., cyclic amines such asN-methylmorpholine, pyridine, etc., aromatic amines such asN,N-dimethylaniline, N,N-diethylaniline, etc.), and inorganic bases(e.g., alkali metal carbonates such as sodium carbonate, potassiumcarbonate, etc., alkali metal hydrogencarbonates such as sodiumhydrogencarbonate, potassium hydrogencarbonate, etc.). The amount of thebase to be used is, for example, from 1 to 5 molar equivalents or so,preferably from 1 to 3 molar equivalents or so, relative to mol of thecompound (III) or its reactive derivative. In the reaction of the step(1), employable is a water-immiscible solvent. In this case, water maybe added to the reaction system and the reaction is thus conducted inthe resulting two-phase system.

The reaction time is generally from 1 to 48 hours or so, preferably from1 to 24 hours or so. The reaction temperatures falls generally between-10° C. and 120° C. or so, preferably between about 0° C. and 100° C. orso.

The step (2) is to obtain a closed compound (V) by subjecting thecompound (IV) as formed in the previous step (1) to intramolecularaddition-dehydration. In general, a base is employed in this reaction.The base includes, for example, organic bases (e.g.,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undecen-7-ene (DBU), N-benzyltrimethylammoniumhydroxide (Triton B), etc.), and inorganic bases (e.g., alkoxides suchas sodium methoxide, sodium ethoxide, potassium t-butoxide, etc., alkalimetal hydrides such as sodium hydride, potassium hydride, etc., n-butyllithium, lithium diisopropylamide, etc.). The amount of the base to beused is, for example, from 0.5 to 20 equivalents or so, preferably from1 to 5 equivalents or so, relative to the compound (IV).

The ring-closure reaction is generally conducted in a solvent. Thesolvent includes, for example, those as referred to as employable in thestep (1). The reaction temperature varies, depending on the type of thebase to be used, and falls, for example, between about -80° C. and 200°C. or so, preferably about -50° C. and 150° C. or so. The reaction timevaries, depending on the starting materials, the base, the reactiontemperature and the type of the solvent used, and is, for example, fromabout 10 minutes to 24 hours or so.

In the previous reaction, an intramolecular adduct is formed as theintermediate. In order to promote the dehydration of the intermediate toobtain a compound (V), it is often preferable to previously add adehydrating agent (e.g., p-toluenesulfonic acid, methanesulfonic acid,acetic anhydride, etc.) to the reaction system. It is also preferablethat the intermediate is isolated and thereafter it is dehydrated in thepresence of a dehydrating agent to obtain a compound (V).

The step (3) is to produce a compound (VI) by hydrolyzing the cyanogroup of the N-cyanomethyl group in the compound (V) as formed in thestep (2) into a carboxyl group.

The hydrolysis can be conducted by conventional methods, for example, bytreating the compound (V) in a solvent (e.g., alcohols such as methanol,ethanol, propanol, etc., organic acids such as acetic acid, propionicacid, etc., ethers, etc.) in the presence of an acid (preferably, aninorganic acid such as hydrochloric acid, hydrobromic acid, sulfuricacid, etc.), at a temperature between about 15° C. and 130° C. or so.

The step (4) is to produce a compound (VII) by reducing the carboxylgroup in the compound (V) as formed in the step (3) into a hydroxymethylgroup. The reduction can be conducted by conventional methods, forexample, by converting the carboxyl group in the compound (V) into itsreactive derivative (e.g., any of acid halides, mixed acid anhydrides,active esters, esters, etc.), followed by treating the resultingreactive derivative with a reducing agent (e.g., sodium borohydride,aluminium lithium hydride, etc.) in a solvent (e.g., ethers such astetrahydrofuran, dimethoxyethane, etc.), at a temperature between about0° C. and 100° C. or so.

The step (5) is to produce a lactone compound (VIII) by treating thecompound (VII) as formed in the previous step (4) under an acidiccondition. This step can be conducted under the same conditions as thosefor the foregoing step (3).

The step (6) is to produce an amide compound (IX) by reacting thecompound (VIII) as formed in the previous step (5) with an amine. Thisreaction can be conducted in the absence or presence of a solvent. Thesolvent includes, for example, those as referred to hereinabove asemployable in the foregoing step (1). The amount of the amine to be usedis, for example, from 1 to 50 mols or so, preferably from 1 to 10 molsor so, relative to mol of the compound (VIII). The reaction can beconducted, for example, at a temperature falling between about 15° C.and 200° C. or so, preferably between about 50° C. and 180° C. or so. Asa result of the step (6), a compound (IX) where X is a hydroxyl group isformed.

The step (7) is to obtain a compound (IIa) by converting the hydroxylgroup X in the compound (IX) as formed in the previous step (6) into aremovable group L.

The leaving group L includes, for example, a halogen atom (e.g.,chlorine, bromine and iodine atoms, etc.), a C₁₋₄ alkanesulfonyloxygroup (e.g., methanesulfonyloxy and ethanesulfonyloxy groups, etc.), aC₆₋₁₀ arylsulfonyloxy group (e.g., benzenesulfonyloxy andp-toluenesulfonyloxy groups, etc.), etc. For the conversion, in general,compounds corresponding to the above-mentioned removable group (e.g.,thionyl chloride, thionyl bromide, methanesulfonyl chloride,benzenesulfonyl chloride, etc.) are used. The conversion can beconducted in a solvent (e.g., hydrocarbons such as benzene, toluene,etc., halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane, chloroform, etc., ethers such as tetrahydrofuran,etc., esters such as ethyl acetate, etc.). The reaction temperaturefalls, for example, between about 0° C. and 100° C. or so.

Some of the starting compounds (II) can also be produced in accordancewith known methods for producing the corresponding compounds where RingA and Ring B are both homocyclic rings (for example, a method describedin EP-585913, etc.) or with reference thereto.

In addition, the compounds of formula (IIa) can also be produced, withreference to the above-mentioned known methods (for example, a methoddescribed in EP-481383A1, etc.), via the following compounds (XII)wherein --X . . . . . Y-- is --CO--O--. For example, compounds of thefollowing general formula (IIb) can be produced according to thefollowing reaction process (2). ##STR50##

In these formulae, the symbols have the same meanings as above.

In the reaction process (2), the steps (1) through (4) can be conductedwith reference to known methods for producing the correspondingcompounds where Ring A and Ring B are both optionally substitutedbenzene rings (for example, a method described in EP-481383A1, etc.).The steps (5) and (6) are to amidate the carboxyl group in a compound(XII) and a compound (XIII)., which can be conducted in the same manneras in the step (1) in the above-mentioned reaction process (1). The step(7) is to convert the pyran ring in the compound (XIV) as formed in thestep (5) into a pyridine ring, which can be conducted in the same manneras in the step (4) (see N. A. Santagati, E. Bousquet, G. Romeo, A.Garuso and A. Prato; Bolletino Chimica Farmaceutico, Vol. 125, p. 437,1986).

Of the starting compounds (II), those of the following formula (IIc):##STR51## wherein --N═CC< corresponds to --X . . . . . Y<, and the othersymbols have the same meanings as above, can be produced by thecombination of known methods for producing the correspondingquinoline-skeleton compounds where Ring A and Ring B are both benzenerings (for example, methods described in EP-354994A2, EP-304063A2, etc.)and the methods for producing the above-mentioned compounds (IIa) and(IIb), etc.

Of the compounds (II), those where Ring A and/or Ring B is/arenon-aromatic, nitrogen-containing heterocyclic ring(s) can be producedby reducing the corresponding aromatic rings according to theabove-mentioned reduction.

The compounds (II) may form salts, which include, for example, saltswith inorganic acids (e.g., hydrochloric acid, phosphoric acid,hydrobromic acid, sulfuric acid, etc.), salts with organic acids (e.g.,acetic acid, formic acid, propionic acid, fumaric acid, maleic acid,succinic acid, tartaric acid, citric acid, malic acid, oxalic acid,benzoic acid, methanesulfonic acid, benzenesulfonic acid,toluenesulfonic acid, etc.), etc. Where the compounds (II) have acidicgroup(s) such as carboxyl group(s), etc., they may also form salts withinorganic bases (e.g., alkali metals such as sodium, potassium, etc.,alkaline earth metals such as calcium, magnesium, etc., ammonia, etc.)or with organic bases (e.g., tri-C₁₋₃ alkylamines such astrimethylamine, triethylamine, etc.).

The compounds represented by the above-mentioned general formula (I),(Ia) also can be produced by, for example, the following reactionprocess (3). ##STR52## [wherein all symbols are of the same meaning asdefined above, and L' stands for a halogen atom (e.g., chlorine, bromineand iodine atoms, etc.), a substituted sulfonyloxy group (e.g.,methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy andp-toluenesulfonyloxy groups, etc.), etc.].

The above-illustrated reaction process (3) is alkylation using analkylating agent in the presence of a base.

The alkylation is conducted, employing approximately 1 to 3 moles eachof the base and the alkylating agent relative to one mole of thecompound (XV), usually in a solvent for example halogenated hydrocarbonssuch as dichloromethane, chloroform, etc., nitriles such asacetonitrile, etc., ethers such as dimethoxyethane, tetrahydrofuran,etc., aprotic polar solvents such as dimethylformamide,dimethylsulfoxide, hexamethylphosphoramide, etc.

Addition of a base to the reaction system advantageously promotes thereaction. As the base, for example, advantageously employed is any ofinorganic bases (alkali metal hydroxides such as sodium hydroxide,potassium hydroxide, etc.; alkali metal hydrogencarbonates such assodium hydrogencarbonate, potassium hydrogencarbonate, etc.; alkalimetal carbonates such as sodium carbonate, potassium carbonate, etc.;alkali metal hydrides such as sodium hydride, potassium hydride, etc.;sodium amide; alkoxides such as sodium methoxide, sodium ethoxide,etc.), and organic bases (amines such as trimethylamine, triethylamine,diisopropylethylamine, etc.; cyclic amines such as pyridine, etc.).

As the alkylating agent, use is made of, for example, substitutedhalides (e.g. chloride, bromide and iodide) and a substitutedsulfonyloxy group (e.g., methanesulfonyloxy, ethanesulfonyloxy,benzensulfonyloxy and p-toluenesulfonyloxy groups, etc.), etc.

While the reaction conditions vary with the combination of the base andthe alkylating agent then employed, it is preferable to conduct thereaction usually at 0° C. to room temperature for about 1-10 hours.

In the reactions of producing the final compounds and the startingcompounds, if the raw materials used have, as substituent(s), aminogroup(s), carboxyl group(s) and/or hydroxyl group(s), such groups mayoptionally be protected by ordinary protecting groups such as thosegenerally employed in peptide chemistry, etc. In such cases, if desired,the protecting groups are optionally removed after the reactions toobtain the intended compounds.

The protecting group for amino groups includes, for example, a C₁₋₆alkylcarbonyl group (e.g., formyl, methylcarbonyl and ethylcarbonylgroups, etc.), a phenylcarbonyl group, a C₁₋₆ alkyl-oxycarbonyl group(e.g., methoxycarbonyl and ethoxycarbonyl groups, etc.), anaryloxycarbonyl group (e.g., phenyloxycarbonyl group, etc.), a C₇₋₁₀aralkyl-carbonyl group (e.g., phenyl-C₁₋₄ alkyl-carbonyl such asbenzylcarbonyl group, etc.), a trityl group, a phthaloyl group, etc.These protecting groups may optionally be substituted. As substituentsfor these protecting groups, for example, mentioned are a halogen atom(e.g., fluorine, chlorine, bromine and iodine atoms), a C₁₋₆alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl andbutylcarbonyl groups, etc.), a nitro group, etc. The number of thesubstituents is from 1 to 3 or so.

The protecting group for carboxyl groups includes, for example, C₁₋₆alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl andtert-butyl groups, etc.), a phenyl group, a trityl group, a silyl group,etc. These protecting groups may optionally be substituted. Assubstituents for these protecting groups, for example, mentioned are ahalogen atom (e.g., fluorine, chlorine, bromine and iodine atoms), aC₁₋₆ alkylcarbonyl group (e.g., formyl, methylcarbonyl, ethylcarbonyland butylcarbonyl groups, etc.), a nitro group, etc. The number of thesubstituents is from 1 to 3 or so.

The protecting group for hydroxyl groups includes, for example, C₁₋₆alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl andtert-butyl groups, etc.), a phenyl group, a C₇₋₁₀ aralkyl group (e.g.,benzyl group, etc.), a C₁₋₆ alkylcarbonyl group (e.g., formyl,methylcarbonyl and ethylcarbonyl groups, etc.), an aryloxycarbonyl group(e.g., phenyloxycarbonyl group, etc.), a C₇₋₁₀ aralkyl-carbonyl group(e.g., benzyloxycarbonyl group, etc.), a pyranyl group, a furanyl group,a silyl group, etc. These protecting groups may optionally besubstituted. As substituents for these protecting groups, for example,mentioned are a halogen atom (e.g., fluorine, chlorine, bromine andiodine atoms), a C₁₋₆ alkylcarbonyl group, a phenyl group, a C₇₋₁₀aralkyl group, a nitro group, etc. The number of the substituents isfrom 1 to 4 or so.

To remove the protecting groups, known methods are employable or arereferred to. For example, employable are methods of treating theprotected compounds with acids, bases, reducing agents, ultravioletrays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,tetrabutylammonium fluoride, palladium acetate or the like.

The compounds (I) and (Ia) thus produced according to the methodsmentioned hereinabove can be isolated and purified by ordinaryseparation means, for example, by recrystallization, distillation,chromatography, etc. Where the compounds (I) thus produced are of freeforms, they can be converted into their salts in accordance with or withreference to known methods (for example, neutralization, etc.). On thecontrary, if the compounds (I) are obtained as their salts, they can beconverted into the corresponding free forms in accordance with or withreference to known methods.

The compounds (I) and (Ia) or salts thereof of the present inventionhave tachykinin receptor (especially SP and/or NKA receptor(s))antagonistic activity in vitro, and have the function of inhibiting thetracheal plasma extravasation induced by capsaicin (in vivo). Capsaicin(a main ingredient of the burning taste of red pepper) is known as asubstance that liberates endogenous neuropeptides, such as SP, NKA andcalcitonin gene-related peptide(CGRP) by stimulating C-fiber primarysensory nerve that contains such neuropeptides. Thus, the inhibitoryaction of the plasma extravasation of the compounds (I) and (Ia) or saltthereof of the present invention is considered to be based on theantagonistic activity toward tachykinin receptor.

In addition, the compounds (I) and (Ia) or salts thereof of the presentinvention are safe as having low toxicity.

Therefore, the compounds (I) and (Ia) or salts thereof of the presentinvention, thus having such an excellent tachykinin receptorantagonistic effect, are usable as safe medicines for preventing andtreating various disorders in mammals (e.g., mice, rats, hamsters,rabbits, cats, dogs, bovines, sheep, monkeys, man, etc.), such asinflammations or allergic disorders (e.g., atopy, dermatitis, herpes,proriasis, asthma, bronchitis, expectoration, rhinitis, rheumatoidarthritis, osteoarthritis, osteoporosis, multiple sclerosis,conjunctivitis, cystitis, etc.), pain, migraine, neuralgia, pruritus,cough, and additionally disorders of central nervous systems [e.g.,schizophrenia, Parkinson's disease, psychosomatic disorders, dementia(e.g., Alzheimer's disease, etc.), etc.], digestive diseases (forexample, irritable bowel syndrome, ulcerative colitis, Crohn's disease,diseases caused by a spiral urease-positive gram-negative bacterium suchas Helicobacter pylori, etc.), emesis, disorders of micturition (forexample, pollakisuria, urinary incontinence etc.), disturbances ofcirculation (for example, angina pectories, hypertension, cardiacinsufficiency, thrombosis, etc.) and immunopathy, etc. Moreparticularly, the compounds (I) and (Ia) or salts thereof of the presentinvention are usable as a tachykinin receptor antagonist and as anameliorative preparation for disorders of micturition such aspollakisuria urimary incontinence, etc., and even as medicines fortreating such disorders of micturition.

Pharmaceutical preparations comprising compounds (I) and (Ia) or saltsthereof of the present invention may be in any solid forms of powders,granules, tablets, capsules, etc., and in any liquid forms of syrups,emulsions, injections, etc.

The preventive and remedial preparations of the present invention can beproduced by any conventional methods of, for example, blending,kneading, granulation, tabletting, coating, sterilization,emulsification, etc., in accordance with the forms of the preparationsto be produced. For the production of such pharmaceutical preparations,for example, referred to are the particular items in the general remarksfor pharmaceutical preparations in the Japanese Pharmacopeia.

In the pharmaceutical preparations of the present invention, the contentof the compounds (I) and (Ia) or salts thereof is, though varyingdepending on the forms of the preparations, generally from 0.01 to 100%by weight or so, preferably from 0.1 to 50% by weight or so, morepreferably from 0.5 to 20% by weight or so, relative to the total weightof each preparation.

Where the compounds (I) and (Ia) or salts thereof of the presentinvention are used in medicines such as those mentioned above, they are,either directly or after having been mixed with suitable,pharmaceutically-acceptable carriers, for example, vehicles (e.g.,starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.),binders (e.g., starch, arabic gum, carboxymethyl cellulose,hydroxypropyl cellulose, crystalline cellulose, alginic acid, gelatin,polyvinyl pyrrolidone, etc.), lubricants (e.g., stearic acid, magnesiumstearate, calcium stearate, talc, etc.), disintegrators (e.g., calciumcarboxymethyl cellulose, talc, etc.), diluents (e.g., water forinjection, physiological saline, etc.) and optionally with additives(e.g., stabilizer, preservative, colorant, fragrance, dissolution aid,emulsifier, buffer, isotonic agent, etc.), etc., by ordinary methods,formulated into solid preparations such as powders, fine granules,granules, tablets, capsules, etc., or into liquid preparations such asinjections, etc., for peroral or parenteral administration. The dose ofthe pharmaceutical preparation of the present invention varies,depending on the kind of the compounds (I) and (Ia) orpharmaceutically-acceptable salts thereof, the administration route, thecondition and the age of patients, etc. For example, the dose for oraladministration of the pharmaceutical preparation to an adult patientsuffering from disorders of micturition is, in general, from about 0.005to 50 mg/kg/day, preferably from about 0.05 to 10 mg/kg/day, morepreferably from about 0.2 to 4 mg/kg/day, in terms of the compound (I)or (Ia) or its salt, which may be administered once a day or in two orthree portions a day.

The compounds (I) and (Ia) or salts thereof of the present invention maybe optionally blended with any desired amounts of any otherpharmaceutically-active ingredients to formulate pharmaceuticalpreparations. Such active ingredients include, for example, drugs forcentral nervous systems (e.g., imipramine, etc.), anti-cholinergic drugs(e.g., oxybutynin, etc.), α₁ -receptor-blocking drugs (e.g., tamsulosin,etc.), muscle relaxants (e.g., baclofen, etc.), potassiumchannel-opening drugs (e.g., nicorandil, etc.), potassiumchannel-blocking drugs (e.g., nifedipine, etc.), etc.

The compounds (I) and (Ia) or salts thereof of the present inventionhave a high tachykinin receptor antagonistic effect, especially a highsubstance P receptor antagonistic effect, while having low toxicity, andare safe as medicines. Therefore, the above-mentioned compounds (I) and(Ia) or salts thereof are usable in pharmaceutical compositions,tachykinin receptor antagonists and ameliorative preparations fordysuria.

The present invention will be described in more detail hereinunder, withreference to Examples and Referentce Examples. However, the presentinvention is not restricted by these examples, and changes andmodifications can be made within the range which does not deviate thescope of the present invention.

Elution in the column chromatography in the following Reference Examplesand Examples was conducted under observation by TLC (thin layerchromatography), unless otherwise specifically indicated. In the TLCobservation, 60F₂₅₄ produced by Merck Co. was used as the TLC plate, andthe solvent employed in the column chromatography was used as thedeveloping eluent. For the detection, a UV detector was used. As silicagel for the column chromatography, Silica Gel 60 (70-230 mesh) producedby Merck Co. was used. Room temperature as referred to hereinundergenerally means temperatures falling between about 10° C. and about 35°C. For dring the extract solutions, sodium sulfate or magnesium sulfatewas used.

The meanings of the abbreviations as used in the following Examples andReferential Examples are as follows:

NMR: Nuclear magnetic resonance spectrum

EI-MS: Electron impact mass spectrum

SI-MS: Secondary ionization mass spectrum

DMF: Dimethylformamide

THF: Tetrahydrofuran

DMSO: Dimethylsulfoxide

Hz: Herz

J: coupling constant

m: multiplet

q: quartet

t: triplet

d: doublet

s: singlet

b: broad

like: approximate

EXAMPLE 1

7-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9-tetrahydro-5-(4-methylphenyl)-6,11-dioxo-11H-pyrazino[2,1-g][1,7]naphthyridine

A mixture of the compound (200 mg) as obtained in Reference Example 1,triethylamine (0.20 ml), methanesulfonyl chloride (0.10 ml) anddichloromethane (10 ml) was stirred at 0° C. for 2 hours. Ethyl acetatewas added to the reaction mixture, which was then washed with water anddried. The solvent was evaporated to giveN-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-7-(2-methanesulfonyloxyethyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide.This compound was dissolved in DMF (5 ml), and sodium hydride (60% oily)(30 mg) was added thereto and stirred for 1.5 hours at room temperature.The reaction mixture was diluted with ethyl acetate, washed successivelywith water, diluted hydrochloric acid and water, and dried. After thesolvent was removed by distillation, the entitled compound was obtainedas colorless crystals (109 mg).

m.p. 270-271° C. (recrystallized from ethyl acetate-ethyl ether)

NMR (200 MHz, CDCl₃) ppm: 2.46 (3H, s), 3.67 (2H, t like, J=5.4 Hz),4.51 (2H, t like, J=5.4 Hz), 4.81 (2H, s), 7.13 (2H, d, J=8.1 Hz), 7.33(2H, d, J=8.1 Hz), 7.52 (1H, dd, J=8.4, 4.4 Hz), 7.64 (1H, dd, J=8.4,1.6 Hz), 7.70 (2H, s), 7.84 (1H, s), 8.97 (1H, dd, J=4.4, 1.6 Hz)

Elemental Analysis for C₂₇ H₁₉ N₃ O₂ F₆ : Calcd.(%): C, 61.02; H,3.60;.N, 7.91 Found (%): C, 61.07; H, 3.50; N, 7.85

Example 2

7-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9,10,12-hexahydro-5-(4-methylphenyl)-6,12-dioxo[1,4]diazepino[2,1-g][1,7]naphthyridine

A mixture ofN-[3,5-bis(trifluoromethyl)benzyl]-7-(3-chloropropyl)-7,8-dihydro-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide(66 mg), sodium hydride (60% oily) (84 mg) and THF (3 ml) was stirred atroom temperature for 14 hours. 2N-HCl was added to the reaction mixture,which was then made basic with aqueous potassium carbonate andthereafter extracted with ethyl acetate. The extract was washed withwater and dried, and the solvent was removed by distillation. Thus, theentitled compound was obtained as colorless crystals (35 mg).

m.p. 194-195° C. (recrystallized from ethyl acetate-isopropyl ether)

NMR (200 MHz, CDCl₃) ppm: 2.16 (2H, m), 2.42 (3H, s), 3.25-3.70 (3H, m),4.12 (1H, d, J=15 Hz), 5.34 (1H, d, J=15 Hz), 5.52 (1H, m), 6.93 (1H, d,J=8.2 Hz), 7.20 (1H, d, J=8.2 Hz), 7.30-7.45 (2H, m), 7.51 (1H, dd,J=8.4,4.4 Hz), 7.62 (2H, s), 7.70 (1H, dd, J=8.4, 1.6 Hz), 7.84 (1H, s),8.93 (1H, dd, J=4.4, 1.6 Hz)

Elemental Analysis for C₂₈ H₂₁ N₃ O₂ F₆ : Calcd.(%): C, 61.65; H, 3.88;N, 7.70 Found (%): C, 61.29; H, 4.06; N, 7.61

Example 3

7-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9,10,11-hexahydro-5-(4-methylphenyl)-6,13-dioxo-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 5 was reacted and treatedin the same manner as in Example 1 to obtain the entitled compound ascolorless crystals.

m.p. 192-193° C. (recrystallized from ethyl acetate-isopropyl ether)

NMR (200 MHz, CDCl₃) ppm: 1.7-2.5 (4H, m), 2.37 (3H, s), 3.25 (1H, m),3.40-3.72 (2H, m), 4.01 (1H, d, J=15 Hz), 5.13 (1H, dd, J=14, 5.4 Hz),5.46 (1H, d, J=15 Hz), 6.85 (1H, d, J=7.9 Hz), 7.05 (1H, d, J=7.9 Hz),7.26 (1H, d, J=7.8 Hz), 7.34 (1H, d, J=7.8 Hz), 7.42-7.60 (2H, m), 7.47(2H, s), 7.81 (1H, s), 8.92 (1H, m)

Example 4

6,7,8,9,10,12-Hexahydro-7-(2-methoxybenzyl)-5-(4-methylphenyl)-6,12-dioxo[1,4]diazepino[2,1-g)[1,7]naphthyridine

The compound as obtained in Reference Example 6 was reacted and treatedin the same manner as in Example 1 to obtain the entitled compound ascolorless crystals.

m.p. 264-266° C. (recrystallized from ethyl acetate-ethyl ether)

NMR (200 MHz, CDCl₃) ppm: 1.7-2.1 (2H, m), 2.43 (3H, s), 3.25-3.52 (3H,m), 3.84 (3H, s), 4.67 (2H, s), 5.39 (1H, dd, J=14, 5.8 Hz), 6.85-7.00(3H, m), 7.10-7.22 (2H, m), 7.22-7.44 (3H, m), 7.48 (1H, dd, J=8.4, 4.4Hz), 7.72 (1H, dd, J=8.4, 1.4 Hz), 8.90 (1H, dd, J=4.4, 1.4 Hz)

Example 5

6,7,8,9,10,11-Hexahydro-7-(2-methoxybenzyl)-5-(4-methylphenyl)-6,13-dioxo-13H-(1,4]diazocino[2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 7 was reacted and treatedin the same manner as in Example 1 to obtain the entitled compound ascolorless crystals.

m.p. 235-235° C. (recrystallized from ethyl acetate)

NMR (200 MHz, CDCl₃) ppm: 1.6-2.3 (4H, m), 2.46 (3H, s), 3.15-3.30 (1H,m), 3.38-3.65 (2H, m), 3.80 (3H, s), 4.24 (1H, d, J=15 Hz), 5.04 (1H, d,J=15 Hz), 5.13 (1H, dd, J=15, 6.4 Hz), 6.25 (1H, dd, J=7.6, 1.4 Hz),6.63 (1H, dt, J_(d) =0.5 Hz, J_(t) =7.6 Hz), 6.82 (1H, d, J=7.4 Hz),6.96 (1H, dd, J=7.6, 2.0 Hz), 7.11-7.34 (3H, m), 7.38-7.47 (1H, m), 7.47(1H, dd, J=8.3, 4.3 Hz), 7.62 (1H, dd, J=8.3, 1.7 Hz), 8.90 (1H, dd,J=4.3, 1.7 Hz)

Example 6

7-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9,10,11,12,14-octahydro-5-(4-methylphenyl)-6,14-dioxo[1,4]diazonino[2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 8 was reacted and treatedin the same manner as in Example 1 to obtain the entitled compound ascolorless crystals.

m.p. 177-179° C. (recrystallized from ethyl acetate-isopropyl ether)

NMR (200 MHz, CDCl₃) ppm: 1.45-1.95 (4H, m), 2.10 (2H, m), 2.33 (3H, s),3.06-3.24 (1H, m), 3.32-3.56 (2H, m), 3.86 (1H, d, J=15 Hz), 4.95 (1H,dt, J_(d) =15 Hz, J_(t) =4.8 Hz), 5.38 (1H, d, J=15 Hz), 6.86 (1H, dd,J=8.0, 1.5 Hz), 7.00 (1H, d, J=8.0 Hz), 7.17 (1H, d, J=8.2 Hz), 7.29(1H, dd, J=8.2, 1.5 Hz), 7.40-7.54 (2H, m), 7.44 (2H, s), 7.79 (1H, s),8.89 (1H, dd, J=3.8, 2.0 Hz)

Example 7

7-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9,10,12-hexahydro-6,12-dioxo-5-phenyl[1,4)diazepino[2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 9 was reacted and treatedin the same manner as in Example 1 to obtain the entitled compound ascolorless crystals.

m.p. 244-245° C. (recrystallized from ethyl acetate-THF-ethyl)

NMR (200 MHz, CDCl₃) ppm: 2.00-2.25 (2H, m), 3.25-3.70 (3H, m), 4.15(1H, d, J=15 Hz), 5.30 (1H, d, J=15 Hz), 5.52 (1H, m), 7.05 (1H, d,J=7.4 Hz), 7.3-7.7 (6H, m), 7.62 (2H, s), 7.84 (1H, s), 8.93 (1H, dd,J=4.2, 1.6 Hz)

Example 8

7-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9,10,11-hexahydro-6,13-dioxo-5-phenyl-13H-[1,4]diazocino(2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 10 was reacted and treatedin the same manner as in Example 1 to obtain the entitled compound ascolorless crystals.

m.p. 205-206° C. (recrystallized from ethyl acetate-ethyl ether)

NMR (200 MHz, CDCl₃) ppm: 1.70-2.35 (4H, m), 3.18-3.36 (1H, m), 3.4-3.7(2H, m), 3.98 (1H, d, J=15 Hz), 5.14 (1H, dd, J=14, 5.8 Hz), 5.43 (1H,d, J=15 Hz), 6.94 (1H, d, J=7.3 Hz), 7.19 (1H, t, J=7.3 Hz), 7.3-7.6(5H, m), 7.44 (2H, s), 7.79 (1H, s), 8.91 (1H, dd, J=4.0, 1.8 Hz)

Example 9

7-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9,10,11-hexahydro-5-(4-methylphenyl)-6,13-dioxo-13H-[1,4]diazocino[1,2-b][2,7]naphthyridine

The compound as obtained in Reference Example 11 was reacted and treatedin the same manner as in Example 1 to obtain the entitled compound ascolorless crystals.

m.p. 231-233° C. (recrystallized from THF-isopropyl ether)

NMR (200 MHz, CDCl₃) ppm: 1.7-2.3 (4H, m), 2.37 (3H, s), 3.2-3.7 (3H,m), 4.00 (1H, d, J=15 Hz), 5.05 (1H, dd, J=15, 6.2 Hz), 5.44 (1H, d,J=15 Hz), 6.83 (1H, dd, J=7.8, 1.6 Hz), 6.98 (1H, d, J=5.4 Hz), 7.04(1H, d, J=7.8 Hz), 7.25 (1H, d, J=7.8 Hz), 7.33 (1H, dd, J=7.8, 1.6 Hz),7.46 (2H, s), 7.81 (1H, s), 8.64 (1H, d, J=5.4 Hz), 9.68 (1H, s)

Example 10

7-[3,5-Bis(trifluoromethyl)benzyl]-1,2,3,4,6,7,8,9,10,11-decahydro-2-methyl-5-(4-methylphenyl)-6,13-dioxo-13H-[1,4]diazocino[1,2-b][2,7]naphthyridine

A mixture of the compound (250 mg) as obtained in Example 9, iodomethane(3 ml) and ethyl acetate (6 ml) was heated under reflux for 1.5 hours.After the solvent was removed by distillation, the residue was dissolvedin methanol (15 ml). Sodium borohydride (50 mg) was added to theresulting solution at 0° C. with stirring, and the mixture was thenfurther stirred at 0° C. for one hour and thereafter concentrated. Ethylacetate was added to the resulting concentrate, which was then washedwith water and dried. Then, the solvent was removed by distillation. Theresidue was dissolved in methanol (15 ml), and 10% palladium-carbon (50%hydrous) (100 mg) was added thereto and stirred in a hydrogen atmosphereat room temperature for 3 hours. The catalyst was removed by filtration,and the solvent was removed from the filtrate by distillation. Theresidue was subjected to column chromatography (ethyl acetate--ethylacetate:methanol=4:1) using silica gel, and the entitled compound wasobtained as pale yellow crystals (150 mg).

m.p. 233-235° C. (recrystallized from THF-ethyl acetate-isopropyl ether)

NMR (200 MHz, CDCl₃) ppm: 1.7-2.6 (8H, m), 2.31 (3H, s), 2.47 (3H, s),3.1-3.8 (5H, m), 3.95 (1H, d, J=15 Hz), 4.93 (1H, dd, J=14, 6.2 Hz),5.41 (1H, d, J=15 Hz), 6.72 (1H, d, J=7.8 Hz), 6.98 (1H, d, J=7.8 Hz),7.19 (2H, s), 7.42 (2H, s), 7.78 (1H, s)

Example 11

4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

Sodium hydride (60% oily) (60 mg) was added to a THF (15 ml) solution ofN-[3,5-bis(trifluoromethyl)benzyl]-2-chloro-N-(2-hydroxyethyl)-4-phenyl-3-pyridinecarboxamide(Reference Example 12) (348 mg) and the mixture was stirred for 2 hourswhile heating under reflux. Ethyl acetate was added to the reactionmixture, which was then washed with water and dried. After the solventwas removed by distillation, the entitled compound was obtained ascolorless crystals (278 mg).

m.p. 200-201° C. (recrystallized from ethanol-hexane)

NMR (200 MHz, CDCl₃) ppm: 3.70 (2H, t, J=5.8 Hz), 4.47 (2H, t, J=5.8Hz), 4.88 (2H, s), 7.24 (1H, d, J=5.2 Hz), 7.25-7.55 (5H, m), 7.80 (2H,s), 7.86 (1H, s), 8.44 (1H, d, J=5.2 Hz)

EI-MS m/z: 466 (M⁺) [(C₂₃ H₁₆ N₂ O₂ F₆)⁺ ]

Example 12

(9R)-7-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9,10,12-hexahydro-9-methyl-5-(4-methylphenyl)-6,12-dioxo[1,4]diazepino[2,1-g][1,7]naphthyridine

A mixture of the compound (700 mg) as obtained in Reference Example 13,triethylamine (0.41 ml), methanesulfonyl chloride (0.224 ml) and THF (15ml) was stirred at room temperature for 30 minutes, and a saturatedaqueous sodium hydrogencarbonate solution (15 ml) was added thereto andagain stirred for 30 minutes at room temperature. The reaction mixturewas extracted with ethyl acetate, the extract was washed with dilutedhydrochloric acid and a saturated aqueous sodium chloride solution anddried, and the solvent was removed by distillation. The residue wasdissolved in THF (15 ml), and then sodium hydride (60% oily) (76 mg) wasadded thereto and stirred at room temperature for 1.5 hours. Thereaction mixture was diluted with ethyl acetate, washed with dilutedhydrochloric acid, aqueous sodium carbonate and a saturated aqueoussodium chloride solution and then dried, and the solvent was removed bydistillation. The residue was subjected to column chromatography (ethylacetate:methanol=9:1) using silica gel, and the entitled compound wasobtained as colorless crystals (408 mg).

m.p. 179-180° C. (recrystallized from ethyl acetate-isopropyl ether)

NMR (200 MHz, CDCl₃) ppm: 1.05 (2Hx2/3, d, J=7.0 Hz), 1.22 (3Hx1/3, d,J=7.0 Hz), 2.39 (3Hx1/3, s), 2.42 (3Hx2/3, s), 2.52 (1H, m), 3.0-3.3(2H, m), 3.48 (1Hx2/3, dd, J=14, 4.6 Hz), 3.71 (1Hx1/3, dd, J=16, 5.2Hz), 4.06 (1Hx1/3, d, J=15 Hz), 4.12 (1Hx2/3 ,d, J=15 Hz), 5.28-5.65(2H, m), 6.83 (1Hx1/3, d, J=7.4 Hz), 6.96 (1Hx2/3, d, J=7.6 Hz), 7.09(1Hx1/3, d, J=7.4 Hz), 7.20 (1Hx2/3,d, J=7.6 Hz), 7.35(2H,m),7.42-7.75(4H,m), 7.83(1H,s), 8.92(1H,d,J=3.6Hz) Elemental Analysis forC₂₉ H₂₃ N₃ O₂ F₆ : Calcd.(%): C, 62.25; H, 4.14; N, 7.51. Found (%): C,62.00; H, 4.08; N, 7.24. [α]_(D) : -60.2° (c=0.348, MeOH)

Example 13

(9S)-7-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9,10,12-hexahydro-9-methyl-6,12-dioxo-5-phenyl[1,4]diazepino[2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 14 was reacted and treatedin the same manner as in Example 12 to obtain the entitled compound ascolorless crystals. m.p. 150-152° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 1.06(3H×2/3,d,J=7.0Hz), 1.21(3H×1/3,d,J=7.0 Hz), 2.50(1H,m), 3.05-3.30(2H,m),3.49(1H×2/3,dd,J=14,4.6 Hz), 3.72(1H×1/3,dd,J=16,5.4 Hz),4.07(1H×1/3,d,J=15 Hz), 4.14(1H×2/3,d,J=15 Hz), 5.25-5.62(2H,m),6.94(1H×1/3,d,J=7.6 Hz), 7.08(1H×2/3,d,J=7.4 Hz), 7.2-7.7(8H,m),7.83(1H,s), 8.93(1H,dd,J=4.3,1.7 Hz) Elemental Analysis for C₂₈ H₂₁ N₃O₂ F₆ : Calcd.(%): C, 61.65; H, 3.88; N, 7.70. Found (%): C, 61.33; H,3.89; N, 7.51. [α]_(D) : +69.80 (c=0.353, MeOH)

Example 14

(9S)-7-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9,10,12-hexahydro-9-methyl-5-(4-methylphenyl)-6,12-dioxo[1,4]diazepino[2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 15 was reacted and treatedin the same manner as in Example 12 to obtain the entitled compound ascolorless crystals. m.p. 179-180° C. (recrystallized from ethylacetate-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: Same as the spectrumof the compound of Example 12 Elemental Analysis for C₂₉ H₂₃ N₃ O₂ F₆ :Calcd.(%): C, 62.25; H, 4.14; N, 7.51. Found (%): C, 61.94; H, 4.16; N,7.24. [α]_(D) : +58.2° (c=0.353, MeOH)

Example 15

(+/-)-7-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9,10,11-hexahydro-9-methyl-6,13-dioxo-5-phenyl-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine

Methanesulfonyl chloride (0.29 ml) was added to a THF (15 ml) solutionof the compound (830 mg) as obtained in Reference Example 16 andtriethylamine (0.56 ml) with stirring and cooling with ice. Theresulting mixture was stirred for 50 minutes, while still cooling withice, and then a saturated aqueous sodium hydrogencarbonate solution (15ml) was added thereto and again stirred for 40 minutes at roomtemperature. The reaction mixture was extracted with ethyl acetate. Theextract was washed with diluted hydrochloric acid and a saturatedaqueous sodium chloride solution and dried, and then the solvent wasremoved by distillation. The residue was dissolved in THF (25 ml), andsodium hydride (60% oily) (90 mg) was added thereto and stirred for onehour with heating under reflux. The reaction mixture was diluted withethyl acetate, washed with diluted hydrochloric acid, aqueous sodiumcarbonate and a saturated sodium chloride solution, and then dried.After the solvent was removed by distillation, the entitled compound wasobtained as colorless crystals (460 mg). m.p. 257-258° C.(recrystallized from ethyl acetate-ethyl ether) NMR(200 MHz, CDCl₃) ppm:0.92(3H,d,J=6.6 Hz), 1.73(1H,m), 1.95-2.40(2H,m), 2.98(1H,d,J=15 Hz),3.30-3.65(2H,m), 3.97(1H,d,J=15 Hz), 5.11(1H,dd,J=14,5.9 Hz),5.43(1H,d,J=15 Hz), 6.93(1H,d,J=7.6 Hz), 7.19(1H,dd,J=7.6,7.0 Hz),7.3-7.6(7H,m), 7.81(1H,s), 8.91(1H,dd,J=4.0,2.0 Hz) Elemental Analysisfor C₂₉ H₂₃ N₃ O₂ F₆ : Calcd.(%): C, 62.25; H, 4.14; N, 7.51. Found (%):C, 61.93; H, 4.05; N, 7.57.

Example 16

(+/-)-7-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9,10,11-hexahydro-9-methyl-5-(4-methylphenyl)-6,13-dioxo-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 17 was reacted and treatedin the same manner as in Example 15 to obtain the entitled compound ascolorless crystals. m.p. 280-281° C. (recrystallized from ethylacetate-THF-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 0.91(3H,d,J=6.8Hz), 1.73(1H,m), 1.95-2.40(2H,m), 2.37(3H,s), 2.97(1H,d,J=15 Hz),3.35-3.62(2H,m), 3.99(1H,d,J=15 Hz), 5.10(1H,dd,J=14,5.3 Hz),5.46(1H,d,J=15 Hz), 6.83(1H,dd,J=7.8,1.6 Hz), 7.05(1H,d,J=7.8 Hz),7.25(1H,d,J=7.8 Hz), 7.34(1H,dd,J=7.8,1.6 Hz), 7.46(1H,dd,J=8.4,4.2 Hz),7.47(2H,s), 7.55(1H,dd,J=8.4,1.8 Hz), 7.81(1H,s), 8.91(1H,dd,J=4.2,1.8Hz) Elemental Analysis for C₃₀ H₂₅ N₃ O₂ F₆ : Calcd.(%): C, 62.83; H,4.39; N, 7.33. Found (%): C, 62.61; H, 4.21; N, 7.12.

Example 17

(9R)-7-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9,10,11-hexahydro-9-methyl-6,13-dioxo-5-phenyl-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 18 was reacted and treatedin the same manner as in Example 15 to obtain the entitled compound ascolorless crystals. m.p. 245-247° C. (recrystallized from ethylacetate-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: Same as the spectrumof the compound of Example 15 [α]_(D) : +133.8° (c=0.51 , MeOH)Elemental Analysis for C₂₉ H₂₃ N₃ O₂ F₆ : Calcd.(%): C, 62.25; H, 4.14;N, 7.51. Found (%): C, 62.13; H, 4.13; N, 7.40.

Example 18

(9R)-7-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9,10,11-hexahydro-9-methyl-5-(4-methylphenyl)-6,13-dioxo-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 19 was reacted and treatedin the same manner as in Example 15 to obtain the entitled compound ascolorless crystals. m.p. 226-228° C. (recrystallized from ethylacetate-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: Same as the spectrumof the compound of Example 16 [α]_(D) : +109.4° (c=0.541, MeOH).Elemental Analysis for C₃₀ H₂₅ N₃ O₂ F₆ : Calcd.(%): C, 62.83; H, 4.39;N, 7.33. Found (%): C, 62.55; H, 4.56; N, 7.10.

Example 19

(9S)-7-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9,10,11-hexahydro-9-methyl-6,13-dioxo-5-phenyl-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 20 was reacted and treatedin the same manner as in Example 15 to obtain the entitled compound ascolorless crystals. m.p. 242-244° C. (recrystallized from ethylacetate-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: Same as the spectrumof the compound of Example 15 [α]_(D) : -130.4° (c=0.496, MeOH).Elemental Analysis for C₂₉ H₂₃ N₃ O₂ F₆ : Calcd.(%): C, 62.25; H, 4.14;N, 7.51. Found (%): C, 62.07; H, 4.15; N, 7.36.

Example 20

(9S)-7-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9,10,11-hexahydro-9-methyl-5-(4-methylphenyl)-6,13-dioxo-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 21 was reacted and treatedin the same manner as in Example 15 to obtain the entitled compound ascolorless crystals. m.p. 227-228° C. (recrystallized from ethylacetate-isopropyl ether) NMR (200 MHz, CDCl₃) ppm: Same as the spectrumof the compound of Example 16 [α]_(D) : -107.1° (c=0.521, MeOH).Elemental Analysis for C₃₀ H₂₅ N₃ O₂ F₆ : Calcd.(%): C, 62.83; H, 4.39;N, 7.33. Found (%): C, 62.55; H, 4.40; N, 7.13.

Example 21

4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenyl-1H-pyrido[2,3-e][1,4]diazepine

A mixture of the compound (370 mg) as obtained in Reference Example 22,anhydrous potassium carbonate (200 mg) and xylene (10 ml) was stirredfor 9 hours with heating under reflux. After the reaction mixture wascooled, water was added thereto. Then, the mixture was extracted withethyl acetate. The extract was washed with water and dried, and thesolvent was removed by distillation. Thus, the entitled compound wasobtained as colorless crystals. m.p. 242-243° C. (recrystallized fromethyl acetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 3.60-3.80(4H,m),4.81(2H,s), 4.86(1H,s), 6.87(1H,d,J=5.2 Hz), 7.30-7.50(6H,m),7.79(2H,s), 7.85(1H,s), 8.21(1H,d,J=5.2 Hz) Elemental Analysis for C₂₃H₁₇ N₃ OF₆ : Calcd.(%): C, 59.36; H, 3.68; N, 9.03. Found (%): C, 59.24;H, 3.66; N, 9.06. EI-MS m/z: 465 (M⁺) [(C₂₃ H₁₇ N₃ OF₆)⁺ ]

Example 22

5-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine

The compound as obtained in Reference Example 23 was reacted and treatedin the same manner as in Example 11 to obtain the entitled compound ascolorless crystals. m.p. 188-189° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 1.65-1.88(1H,m),2.18-2.45(1H,m), 3.36(1H,dd,J=15.2 Hz), 3.73(1H,m), 4.17(1H,d,J=15.2Hz), 4.32(1H,dt,J=12.6,3.6 Hz), 4.67(1H,ddd,J=12.6,5.6,2.4 Hz),5.50(1H,d,J=15.2 Hz), 7.16(1H,d,J=5.2 Hz), 7.20-7.45(5H,m), 7.71(2H,s),7.83(1H,s), 8.41(1H,d,J=5.2 Hz) Elemental Analysis for C₂₄ H₁₈ N₂ O₂ F₆: Calcd.(%): C, 60.00; H, 3.78; N, 5.83. Found (%): C, 59.92; H, 3.76;N, 5.89.

Example 23

4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-7-methyl-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

The compound as obtained in Reference Example 24 was reacted and treatedin the same manner as in Example 11 to obtain the entitled compound ascolorless crystals. m.p. 179-181° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 2.13(3H,s),3.57(2H,t,J=5.8 Hz), 4.42(2H,t,J=5.8 Hz), 4.80(2H,s), 7.16(2H,m),7.47(3H,m), 7.65(2H,s), 7.81(1H,s), 8.32(1H,s)

Example 24

5-[3,5-Bis(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-8-methyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine

The compound as obtained in Reference Example 25 was reacted and treatedin the same manner as in Example 11 to obtain the entitled compound ascolorless crystals. m.p. 180-182° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 1.71(1H,m),2.07(3H,m), 2.28(1H,m), 3.24(1H,dd,J=15.2,3.8 Hz),3.64(1H,dd,J=15.2,12.0 Hz), 4.05(1H,d,J=15.6 Hz), 4.27(1H,dt,J=12.6,3.8Hz), 4.63(1H,ddd,J=12.6,5.4,2.0 Hz), 5.45(1H,d,J=15.6 Hz), 7.38(5H,m),7.54(2H,s), 7.78(1H,s), 8.29(1H,s)

Example 25

(+/-)-7-[3,5-Bis(trifluoromethyl)benzyl)-6,7,8,9,10,12-hexahydro-9-hydroxy-5-(4-methylphenyl)-6,12-dioxo[1,4]diazepino[2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 26 was reacted and treatedin the same manner as in Example 2 to obtain the entitled compound ascolorless crystals. m.p. 282-283° C. (recrystallized from acetone-ethylether) NMR(200 MHz, CDCl₃) ppm: 2.43(3H,s), 3.35-3.63(3H,m),4.02(1H×3/8,d,J=3.5 Hz,--OH), 4.21(1H×3/8,d,J=15 Hz),4.30(1H×5/8,d,J=3.5 Hz,--OH), 4.38(1H×5/8,d,J=15 Hz), 4.60(1H,m),5.24(1H×3/8,d,J=15 Hz), 5.61(1H×5/8,d,J=15 Hz), 5.68(1H,m),6.92(1H,t-like,J=3.8 Hz), 7.19-7.86(8H,m), 8.95(1H,d,J=4 Hz) ElementalAnalysis for C₂₈ H₂₁ N₃ O₃ F₆.1/4H₂ O: Calcd.(%): C, 59.42; H, 3.83; N,7.42. Found (%): C, 59.45; H, 3.74; N, 7.39. EI-MS m/z: 561 (M⁺) ((C₂₈H₂₁ N₃ O₃ F₆)⁺ ]

Example 26

7-Benzyl-6,7,8,9,10,12-hexahydro-6,12-dioxo-5-phenyl[1,4]diazepino[2,1-g][1,7]naphthyridine

N-Benzyl-7,8-dihydro-7-(3-hydroxypropyl)-8-oxo-5-phenyl-6-pyrido[3,4-b]pyridinecarboxamide(this was obtained by reacting the compound as obtained in ReferenceExample 27 with 3-amino-1-propanol and treated in the same manner as inReference Example 13) was reacted and treated in the same manner as inExample 12 to obtain the entitled compound as colorless crystals. m.p.210-212° C. (recrystallized from ethyl acetate-ethyl ether) NMR(200 MHz,CDCl₃) ppm: 1.7-2.2(2H,m), 3.2-3.6(3H,m), 4.30(1H,d,J=14 Hz),4.89(1H,d,J=14 Hz), 5.43(1H,dd,J=14,5.7 Hz), 7.0-7.7(11H,m),7.70(1H,dd,J=8,4,1.6 Hz), 8.92(1H,dd,J=4.4,1.6 Hz)

Example 27

7-Benzyl-6,7,8,9,10,11-hexahydro-6,13-dioxo-5-phenyl-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine

N-Benzyl-7,8-dihydro-7-(5-hydroxybutyl)-8-oxo-5-phenyl-6-pyrido[3,4-b]pyridinecarboxamide(this was obtained by reacting the compound as obtained in ReferenceExample 27 with 4-amino-1-butanol and treated in the same manner as inReference Example 16) was reacted and treated in the same manner as inExample 15 to obtain the entitled compound as colorless crystals. m.p.243-244° C. (recrystallized from acetone-ethyl ether) NMR(200 MHz,CDCl₃) ppm: 1.6-2.3(4H,m), 3.15(1H,m), 3.35-3.65(2H,m), 3.76(1H,d,J=15Hz), 5.15(1H,dd,J=14,5,7 Hz), 5.42(1H,d,J=15 Hz), 6.64(2H,d,J=6.2 Hz),7.0-7.3(4H,m), 7.3-7.7(6H,m), 8.91(1H,dd,J=4.2,1.8 Hz)

Example 28

7-Benzyl-6,7,8,9,10,11,12,14-octahydro-6,14-dioxo-5-phenyl-[1,4]diazonino[2,1-g][1,7]naphthyridine

N-Benzyl-7,8-dihydro-7-(5-hydroxypentyl)-8-oxo-5-phenyl-6-pyrido[3,4-b]pyridinecarboxamide(this was obtained by reacting the compound as obtained in ReferenceExample 27 with 5-amino-1-pentanol and treated in the same manner as inReference Example 16) was reacted and treated in the same manner as inExample 15 to obtain the entitled compound as colorless crystals. m.p.224-226° C. (recrystallized from ethyl acetate-ethyl ether) NMR(200 MHz,CDCl₃) ppm: 1.3-1.9(4H,m), 2.09(2H,m), 2.85-3.05(1H,m), 3.15-3.40(1H,m),3.50(1H,dt,J_(d) =15 Hz,J_(t) =6.4 Hz), 3.64(1H,d,J=15 Hz),4.97(1H,dt,J_(d) =15 Hz,J_(t) =4.8 Hz), 5.48(1H,d,J=15 Hz),6.43(2H,d,J=7.2 Hz), 7.05-7.25(4H,m), 7.3-7.7(6H,m),8.91(1H,dd,J=4.2,1.8 Hz)

Example 29

7-(3,4-Dichlorbenzyl)-6,7,8,9,10,12-hexahydro-6,12-dioxo-5-phenyl[1,4]diazepino[2,1-g][1,7]naphthyridine

N-(3,4-Dichlorobenzyl)-7,8-dihydro-7-(3-hydroxypropyl)-8-oxo-5-phenyl-6-pyrido[3,4-b]pyridinecarboxamide(this was obtained by reacting the compound as obtained in ReferenceExample 28 with 3-amino-1-propanol and treated in the same manner as inReference Example 13) was reacted and treated in the same manner as inExample 12 to obtain the entitled compound as colorless crystals. m.p.224-226° C. (recrystallized from ethyl acetate-ethyl ether) NMR(200 MHz,CDCl₃) ppm: 1.9-2.-3(2H,m), 3.2-3.6(3H,m), 4.01(1H,d,J=15 Hz),5.05(1H,d,J=15 Hz), 5.49(1H,dd,J=13,5.0 Hz), 6.9-7.1(2H,m), 7.25(1H,m),7.38(1H,d,J=8.6 Hz), 7.3-7.8(6H,m), 8.93(1H,d,J=4.0 Hz)

Example 30

7-(3,4-Dichlorbenzyl)-6,7,8,9,10,11-hexahydro-6,13-dioxo-5-phenyl-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine

N-(3,4-Dichlorobenzyl)-7,8-dihydro-7-(5-hydroxybutyl)-8-oxo-5-phenyl-6-pyrido[3,4-b]pyridinecarboxamide(this was obtained by reacting the compound as obtained in ReferenceExample 28 with 4-amino-1-butanol and treated in the same manner as inReference Example 16) was reacted and treated in the same manner as inExample 15 to obtain the entitled compound as colorless crystals. m.p.236-238° C. (recrystallized from acetone-ethyl ether) NMR(200 MHz,CDCl₃) ppm: 1.7-2.3(4H,m), 3.14(1H,m), 3.39-3.60(2H,m), 3.70(1H,d,J=15Hz), 5.14(1H,dd,J=15,5.9 Hz), 5.35(1H,d,J=15 Hz), 6.35(1H,dd,J=8.4,2.0Hz), 7.02(2H,m), 7.18(1H,d,J=8.4 Hz), 7.3-7.6(6H,m),8.91(1H,dd,J=4.0,1.8 Hz)

Example 31

(S)-5-(3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-3,8-dimethyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine

The compound as obtained in Reference Example 29 was reacted and treatedin the same manner as in Example 11 to obtain the entitled compound ascolorless crystals. m.p. 147-148° C. (recrystallized from ethylacetate-hexane) NMR(200 MHz, CDCl₃) ppm: 0.83(3H,d,J=7.4 Hz), 2.07(3H,s), 2.39(1H,m), 2.97(1H,d,J=15.4 Hz), 3.48(1H,m),3.87(1H,dd,J=10.4,12.4 Hz), 4.06(1H,d,J=15.6 Hz), 4.59(1H,dd,J=5.2,12.4Hz), 5.44(1H,d,J=15.4 Hz), 7.37(2H,s), 7.53(2H,s), 7.78(1H,s),8.29(1H,s) Elemental Analysis for C₂₆ H₂₂ N₂ O₂ F₆ : Calcd.(%): C,61.42, H, 4.36, N, 5.51. Found (%): C, 61.30, H, 4.52, N, 5.70. [α]_(D)²⁰ : -106.8° (C=0.257, CHCl₃)

Example 32

(R)-5-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-3,8-dimethyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine

The compound as obtained in Reference Example 30 was reacted and treatedin the same manner as in Example 11 to obtain the entitled compound ascolorless crystals. m.p. 147-149° C. (recrystallized from ethylacetate-hexane) NMR(200 MHz, CDCl₃) ppm: Same as the spectrum of thecompound of Example 31 Elemental Analysis for C₂₆ H₂₂ N₂ O₂ F₆ :Calcd.(%): C, 61.42, H, 4.36, N, 5.51. Found (%): C, 61.26, H, 4.33, N,5.69. [α]_(D) ²⁰ : +102.5° (C=0.573, CHCl₃)

Example 33

4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-methyl-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

The compound as obtained in Reference Example 31 was reacted and treatedin the same manner as in Example 11 to obtain the entitled compound ascolorless crystals. m.p. 151-153° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 2.58(3H,s),3.69(2H,t,J=5.4 Hz), 4.47(2H,d,J=5.4 Hz), 4.87(2H,s), 7.11(1H,s),7.17-7.56(5H,m), 7.80(2H,s), 7.86(1H,s) Elemental Analysis for C₂₄ H₁₈N₂ O₂ F₆.1/4 H₂ O: Calcd.(%): C, 59.44, H, 3.85, N, 5.78. Found (%): C,59.42, H, 3.82, N, 5.84.

Example 34

5-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-9-methyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine

The compound as obtained in Reference Example 32 was reacted and treatedin the same manner as in Example 11 to obtain the entitled compound ascolorless crystals. m.p. 164-165° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 1.79(1H,m),2.30(1H,m), 2.56(3H,s), 3.35(1H,m), 3.77(1H,m), 4.14(1H,d,J=15.2 Hz),4.31(1H,m), 4.65(1H,m), 5.49(1H,d,J=15.2 Hz), 7.02(1H,s),7.20-7.50(5H,m), 7.72(2H,s), 7.83(1H,s). Elemental Analysis for C₂₅ H₂₀N₂ O₂ F₆ : Calcd.(%): C, 60.73, H, 4.08, N, 5.68. Found (%): C, 60.43,H, 4.04, N, 5.74.

Example 35

4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-methyl-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine9-oxide

m-Chloroperbenzoic acid (870 mg) was added to a chloroform (30 ml)solution of the compound (1.20 g) as obtained in Example 33 and stirredfor 20 hours at room temperature. The solvent was removed bydistillation, and aqueous potassium carbonate solution was added to theresidue, which was then extracted with ethyl acetate. The extract waswashed with aqueous potassium carbonate solution and dried, and thesolvent was removed by distillation. Thus, the entitled compound wasobtained as colorless crystals (1.10 g). m.p. 181-183° C.(recrystallized from TFH-isopropyl ether) NMR(200 MHz, CDCl₃) ppm:2.62(3H,s), 3.72(2H,m), 4.65(2H,m), 4.89(2H,s), 7.18(1H,s),7.20-7.50(5H,m), 7.79(2H,s), 7.87(1H,s) Elemental Analysis for C₂₄ H₁₈N₂ O₃ F₆.1/2 H₂ O: Calcd.(%): C, 57.03, H, 3.79, N, 5.54. Found (%): C,57.15, H, 3.77, N, 5.16.

Example 36

5-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-9-methyl-6-oxo-7-phenyl-6H-pyrido[2,3-b)[1,5]oxazocine10-oxide

The compound as obtained in Example 34 was reacted and treated in thesame manner as in Example 35 to obtain the entitled compound ascolorless crystals (727 mg). m.p. 116-118° C. (recrystallized fromethanol-ethyl ether) NMR(200 MHz, CDCl₃) ppm: 1.60-1.82(1H,m),2.42(1H,m), 2.61(3H,s), 3.43(1H,dd,J=6.0,17.0 Hz), 3.81(1H,m),4.18(1H,d,J=15.4 Hz), 4.25(1H,m), 4.78(1H,dd,J=5.2,12.6 Hz),5.52(1H,d,J=15.4 Hz), 7.16(1H,s), 7.18-7.50(5H,m), 7.72(2H,s),7.84(1H,s) Elemental Analysis for C₂₅ H₂₀ N₂ O₃.1/2 H₂ O: Calcd.(%): C,58.31, H, 4.01, N, 5.44. Found (%): C, 58.17, H, 4.38, N, 5.31.

Example 37

8-Acetoxymethyl-4-[3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

A mixture of the compound (939 mg) as obtained in Example 35 and aceticanhydride (25 ml) was heated under reflux for 20 minutes. The solventwas removed by distillation, and aqueous potassium carbonate solutionwas added to the residue, which was then extracted with ethyl acetate.The extract was washed with water and dried, and the solvent was removedby distillation. Thus, the entitled compound was obtained as colorlesscrystals (740 mg). m.p. 122-124° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 2.18(3H,s),3.71(2H,t,J=5.6 Hz), 4.50(2H,t,J=5.6 Hz), 4.88(2H,s), 5.21(2H,s),7.18-7.50(6H,m), 7.79(2H,s), 7.87(1H,s) Elemental Analysis for C₂₆ H₂₀N₂ O₄ F₆ : Calcd.(%): C, 58.00, H, 3.74, N, 5.20. Found (%): C, 57.60,H, 4.02, N, 5.09.

Example 38

9-Acetoxymethyl-5-(3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine

The compound as obtained in Example 36 was reacted and treated in thesame manner as in Example 37 to obtain the entitled compound ascolorless crystals (479 mg). m.p. 156-157° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 1.60-1.95(1H,m),2.00-2.20(1H,m), 2.17(3H,s), 336(1H,m), 3.75(1H,m), 4.14(1H,d,J=15.2Hz), 4.31(1H,m), 4.61(1H,m), 5.20(2H,s), 5.48(1H,d,J=15.2 Hz),7.18(1H,s), 7.20-7.50(5H,m), 7.70(2H,s), 7.83(1H,s) Elemental Analysisfor C₂₇ H₂₂ N₂ O₄ F₆ : Calcd.(%): C, 58.70, H, 4.01, N, 5.07. Found (%):C, 58.81, H, 4.11, N, 5.17.

Example 39

4-[3,5-Bis(trifluoromethyl)benzyl]-8-chloromethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

Phosphorus oxychloride (1.24 ml) and triethylamine (1.85 ml) weredropwise added at the same time to a dichloromethane (100 ml) solutionof the compound (4.40 g) as obtained in Example 35, while stirring atroom temperature. The resulting mixture was heated under reflux for 1hour, and then the solvent was removed by distillation. Aqueouspotassium carbonate solution was added to the residue, which was thenextracted with ethyl acetate-THF. The extract was washed with water anddried, and the solvent was removed by distillation. Thus, the entitledcompound was obtained as colorless crystals (1.44 g). m.p. 183-184° C.(recrystallized from ethyl acetate-isopropyl ether) NMR(200 MHz, CDCl₃)ppm: 3.73(2H,t,J=5.4 Hz), 4.51(2H,t,J=5.4 Hz), 4.66(2H,s), 4.89(2H,s),7.27(1H,s), 7.30-7.55(5H,m), 7.81(2H,s), 7.88(1H,s) Elemental Analysisfor C₂₄ H₁₇ N₂ O₂ F₆ Cl: Calcd.(%): C, 55.99, H, 3.33, N, 5.44. Found(%): C, 55.75, H, 3.53, N, 5.27.

Example 40

4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-methoxymethyl-5-oxo-6-phenylpyrido[3,2-f)[1,4]oxazepine

A mixture of the compound (151 mg) as obtained in Example 39, THF (2ml), methanol (1 ml) and 28% sodium methoxide-methanol solution (1 ml)was stirred for 2 hours at room temperature. The solvent was removed bydistillation, and water was added to the residue, which was thenextracted with ethyl acetate. The extract was washed with water anddried, and the solvent was removed by distillation. Thus, the entitledcompound was obtained as colorless crystals (118 mg). m.p. 139-140° C.(recrystallized from ethyl acetate-isopropyl ether) NMR(200 MHz, CDCl₃)ppm: 3.51(3H,s), 3.71(2H,t,J=5.6 Hz), 4.49(2H,t,J=5.6 Hz), 4.58(2H,s),4.89(2H,s), 7.27(1H,s), 7.30-7.52(5H,m), 7.81(2H,s), 7.87(1H,s)Elemental Analysis for C₂₅ H₂₀ N₂ O₃ F₆ : Calcd.(%): C, 58.83, H, 3.95,N, 5.49. Found (%): C, 58.73, H, 3.95, N, 5.57.

Example 41

4-(3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-(1-methyletoxymethyl)-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

A mixture of the compound (150 mg) as obtained in Example 39, THF (1ml), isopropanol (10 ml) and sodium hydride (60% oily) (120 mg) wasstirred for 3 hours at room temperature. The solvent was removed bydistillation, and water was added to the residue, which was thenextracted with ethyl acetate. The extract was washed with water anddried, and the solvent was removed by distillation. The residue waspurified by column chromatography (hexane:ethyl acetate=1:1) usingsilica gel to obtain the entitled compound as colorless crystals (74mg). m.p. 134-136° C. (recrystallized from ethyl acetate-hexane) NMR(200MHz, CDCl₃) ppm: 1.26(6H,d,J=6.0 Hz), 3.60-3.90(3H,m), 4.48(2H,t,J=5.4Hz), 4.63(2H,s), 4.89(2H,s), 7.27(1H,s), 7.30-7.55(5H,m), 7.81(2H,s),7.87(1H,s) Elemental Analysis for C₂₇ H₂₄ N₂ O₃ F₆ : Calcd.(%): C,60.22, H, 4.49, N, 5.20. Found (%): C, 60.00, H, 4.61, N, 5.07.

Example 42

4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-methylthiomethyl-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

A mixture of the compound (125 mg) as obtained in Example 39, methanol(5 ml) and aqueous 15% sodium methylmercaptan solution (1 ml) wasstirred for 10 minutes at room temperature. The solvent was removed bydistillation, and water was added to the residue, which was thenextracted with ethyl acetate. The extract was washed with water anddried, and the solvent was removed by distillation. Thus, the entitledcompound was obtained as colorless crystals (103 mg). m.p. 165-166° C.(recrystallized from ethyl acetate-isopropyl ether) NMR(200 MHz, CDCl₃)ppm: 2.14(3H,s), 3.72(2H,t,J=5.4 Hz), 3.79(2H,s), 4.49(2H,t,J=5.4 Hz),4.89(2H,s), 7.30-7.50(5H,m), 7.34(1H,s), 7.81(2H,s), 7.87(1H,s)Elemental Analysis for C₂₅ H₂₀ N₂ O₂ SF₆.1/6 H₂ O: Calcd.(%): C, 56.71,H, 3.87, N, 5.29. Found (%): C, 56.67, H, 3.87, N, 5.23.

Example 43

8-Aminomethyl-4-[3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

A mixture of the compound (500 mg) as obtained in Example 39, THF (10ml) and aqueous 25% ammonia (10 ml) was heated in a sealed tube at 120°C. for 1 hour. After cooled, the solvent was removed by distillation,and water was added to the residue, which was then extracted with ethylacetate. The extract was washed with water and dried, and the solventwas removed by distillation. Thus, the entitled compound was obtained ascolorless crystals (443 mg). m.p. 188-191° C. (recrystallized fromTHF-ethyl ether) NMR(200 MHz, CDCl₃) ppm: 3.71(2H,t,J=5.6 Hz),4.00(2H,s), 4.50(2H,t,J=5.6 Hz), 4.89(2H,s), 7.20-7.60(6H,m),7.81(2H,s), 7.87(1H,s) Elemental Analysis for C₂₄ H₁₉ N₃ O₂ F₆ :Calcd.(%): C, 58.19, H, 3.87, N, 8.48. Found (%): C, 58.36, H, 3.81, N,8.00.

Example 44

4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-methylaminomethyl-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

A mixture of the compound (150 mg) as obtained in Example 39 and 40%methylamine-methanol solution was stirred for 30 minutes at roomtemperature. The solvent was removed by distillation, and water wasadded to the residue, which was then extracted with ethyl acetate. Theextract was washed with water and dried, and the solvent was removed bydistillation. Thus, the entitled compound was obtained as colorlesscrystals (115 mg). m.p. 152-154° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 2.50(3H,s),3.70(2H,t,J=5.6 Hz), 3.89(2H,s), 4.48(2H,t,J=5.6 Hz), 4.88(2H,s),7.22-7.50(6H,m), 7.80(2H,s), 7.86(1H,s) Elemental Analysis for C₂₅ H₂₁N₃ O₂ F₆ : Calcd.(%): C, 58.94, H, 4.15, N, 8.25. Found (%): C, 58.71,H, 4.25, N, 8.35.

Example 45

4-[3,5-Bis(trifluoromethyl)benzyl]-8-dimethylaminomethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

Dimethylamine (1 ml) was added to a THF (3 ml) solutin of the compound(150 mg) as obtained in Example 39, and then stirred for 30 minutes atroom temperature. The solvent was removed by distillation, and water wasadded to the residue, which was then extracted with ethyl acetate. Theextract was washed with water and dried, and the solvent was removed bydistillation. Thus, the entitled compound was obtained as colorlesscrystals (128 mg). m.p. 186-188° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 2.33(6H,s),3.60(2H,s), 3.71(2H,t,J=5.6 Hz), 4.49(2H,t,J=5.6 Hz), 4.89(2H,s),7.26(1H,s), 7.30-7.50(5H,m), 7.81(2H,s), 7.86(1H,s) Elemental Analysisfor C₂₆ H₂₃ N₃ O₂ F₆ : Calcd.(%): C, 59.66, H, 4.43, N, 8.03. Found (%):C, 59.43, H, 4.49, N, 7.84.

Example 46

4-[3,5-Bis(trifluoromethyl)benzyl]-8-cyclopropylaminomethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

Cyclopropylamine (0.5 ml) was added to a THF (10 ml) solutin of thecompound (155 mg) as obtained in Example 39, and then heated underreflux for 15 hours. The solvent was removed by distillation, and waterwas added to the residue, which was then extracted with ethyl acetate.The extract was washed with water and dried, and the solvent was removedby distillation. The residue was subjected to column chromatography(ethyl acetate:methanol=9:1) using silica gel, to thereby separate andpurify the product. Thus, the entitled compound was obtained ascolorless crystals (127 mg). m.p. 129-131° C. (recrystallized from ethylacetate-hexane) NMR(200 MHz, CDCl₃) ppm: 0.44(4H,m), 2.19(1H,m),3.69(2H,t,J=5.6 Hz), 3.97(2H,s), 4.48(2H,t,J=5.6 Hz), 4.87(2H,s),7.25(1H,s), 7.26-7.55(5H,m), 7.79(2H,s), 7.86(1H,s) Elemental Analysisfor C₂₇ H₂₃ N₃ O₂ F₆.1/6 H₂ O: Calcd.(%): C, 60.22, H, 4.37, N, 7.80.Found (%): C, 59.98, H, 4.40, N, 7.85.

Example 47

4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-(N-methylpiperazinomethyl)-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

N-Methylpiperazine (1 ml) was added to a THF (1 ml) solutin of thecompound (150 mg) as obtained in Example 39, and then stirred for 15hours at room temperature. The solvent was removed by distillation, andwater was added to the residue, which was then extracted with ethylacetate. The extract was washed with water and dried, and the solventwas removed by distillation. Thus, the entitled compound was obtained ascolorless crystals (105 mg). m.p. 181-182° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 2.30(3H,s),2.48(4H,br), 2.59(4H,br), 3.68(2H,s), 3.71(2H,t,J=5.6 Hz),4.48(2H,t,J=5.6 Hz), 4.89(2H,s), 7.27(1H,s), 7.30-7.50(5H,m),7.81(2H,m), 7.87(1H,s) Elemental Analysis for C₂₆ H₂₈ N₄ O₂ F₆ :Calcd.(%): C, 60.20, H, 4.88, N, 9.68. Found (%): C, 59.96, H, 5.00, N,9.51.

Example 48

8-Acetylaminomethyl-4-[3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

Acetic anhydride (1 ml) was added to a pyridine (3 ml) solutin of thecompound (150 mg) as obtained in Reference Example 43, and then stirredfor 20 minutes at room temperature. The solvent was removed bydistillation, and ethyl acetate was added to the residue. The resultingmixture was washed with 1 N-hydrochloric acid and water and dried, andthen the solvent was removed by distillation. Thus, the entitledcompound was obtained as colorless crystals (113 mg). m.p. 223-224° C.(recrystallized from THF-ethyl ether) NMR(200 MHz, CDCl₃) ppm:2.07(3H,s), 3.72(2H,t,J=5.4 Hz), 4.49(2H,t,J=5.4 Hz), 4.56(2H,d,J=5.4Hz), 4.88(2H,s), 6.62(1H,br), 7.21(1H,s), 7.22-7.55(5H,m), 7.80(2H,s),7.87(1H,s) Elemental Analysis for C₂₆ H₂₁ N₃ O₃ F₆ : Calcd.(%): C,58.10, H, 3.94, N, 7.82. Found (%): C, 58.06, H, 3.97, N, 7.99.

Example 49

4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-methanesulfonylaminomethyl-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

Triethylamine (0.085 ml) and methanesulfonyl chloride (0.050 ml) wereadded to a THF (5 ml) solutin of the compound (150 mg) as obtained inReference Example 43, and then stirred for 1 hour at room temperature.The solvent was removed by distillation, and ethyl acetate was added tothe residue. The resulting mixture was washed with aqueous potassiumcarbonate solution and water and dried, and then the solvent was removedby distillation. Thus, the entitled compound was obtained as colorlesscrystals (108 mg). m.p. 194-195° C. (recrystallized from THF-isopropylether) NMR(200 MHz, CDCl₃) ppm: 2.99(3H,s), 3.72(2H,t,J=5.4 Hz),4.44(2H,d,J=6.0 Hz), 4.48(2H,t,J=5.4 Hz), 4.88(2H,s), 5.55(1H,t,J=6.0Hz), 7.26(1H,s), 7.27-7.50(5H,m), 7.80(2H,s), 7.87(1H,s) ElementalAnalysis for C₂₅ H₂₁ N₃ O₄ SF₆.1/2 H₂ O: Calcd.(%): C, 51.55, H, 3.80,N, 7.21. Found (%): C, 51.43, H, 3.78, N, 7.07.

Example 50

6-[3,5-Bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-3,9-dimethyl-5,10-dioxo-4-phenylpyrido[2,3-f][1,4]diazocine

Triethylamine (0.42 ml) and methanesulfonyl chloride (0.24 ml) wereadded to a THF (15 ml) solutin of the compound (370 mg) as obtained inReference Example 33, and then stirred for 1 hour at room temperature.Aqueous saturated sodium hydrogencarbonate solution (15 ml) was added tothe reaction mixture and further stirred for 40 minutes at roomtemperature. Then, the mixture was extracted with ethyl acetate. Theextract was washed with diluted hydrochloric acid and saturated salinesolution and dried, and then the solvent was removed by distillation.The residue was dissolved in THF (30 ml), and sodium hydride (60% oily)(84 mg) was added thereto and heated under reflux for 40 minutes. Theresulting reaction mixture was diluted with ethyl acetate, then washedwith diluted hydrochloric acid, aqueous sodium carbonate solution andsaturated saline solution, and thereafter the solvent was removed bydistillation. Thus, the entitled compound was obtained as colorlesscrystals (213 mg). m.p. 203-205° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 1.72(1H,dd,J=15,7.2Hz), 2.18(3H,s), 2.75(1H,m), 3.04(3H,s), 3.54(3H,m), 4.09(1H,dd,J=14,7.2Hz), 7.2-7.6(5H,m), 7.48(2H,s), 7.74(1H,s), 8.69(1H,s) ElementalAnalysis for C₂₆ H₂₁ N₃ O₂ F₆.0.2 H₂ O: Calcd.(%): C, 59.48, H, 4.11, N,8.00. Found (%): C, 59.39, H, 4.13, N, 7.83. EI-MS m/z: 521 (M+) [(C₂₆H₂₁ N₃ O₂ F₆)⁺ ]

Example 51

6-[3,5-Bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-9-methyl-5,10-dioxo-4-phenylpyrido[2,3-f][1,4]diazocine

The compound as obtained in Reference Example 34 was reacted and treatedin the same manner as in Example 50 to obtain the entitled compound ascolorless crystals. m.p. 167-169° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 2.05(1H,m),2.87(1H,m), 3.10(3H,s), 3.36(1H,d,J=14 Hz), 3.48(1H,d,J=14 Hz),3.97(1H,m), 4.26(1H,dd,J=15,7.1 Hz), 7.35(3H,m), 7.53(5H,m), 7.71(1H,s),8.81(1H,d,J=5.0 Hz) Elemental Analysis for C₂₅ H₁₉ N₃ O₂ F₆ : Calcd.(%):C, 59.18, H, 3.77, N, 8.28. Found (%): C, 58.90, H, 3.81, N, 8.05.

Example 52

6-Benzyl-5,6,7,8,9,10-hexahydro-3,9-dimethyl-5,10-dioxo-4-phenylpyrido[2,3-f][1,4]diazocine

N-Benzyl-N-(2-hydroxyethyl)-5-methyl-2-methylaminocarbonyl-4-phenyl-3-pyridinecarboxamide(this was prepared by reacting the compound as obtained in ReferenceExample 35 with methylamine and treated in the same manner as in Step 4in Reference Example 33) was reacted and treated in the same manner asin Example 50 to obtain the entitled compound as colorless crystals.m.p. 183-184° C. (recrystallized from ethyl acetate-isopropyl ether)NMR(200 MHz, CDCl₃) ppm: 1.46(1H,dd,J=15,8.1 Hz), 2.17(3H,s),2.69(1H,m), 3.02(3H,s), 3.27(1H,d,J=13 Hz), 3.44(1H,d,J=13 Hz),3.56(1H,m), 4.00(1H,m), 7.01(2H,m), 7.2-7.6(8H,m), 8.68(1H,s) ElementalAnalysis for C₂₄ H₂₃ N₃ O₂ : Calcd.(%): C, 74.78, H, 6.01, N, 10.09.Found (%): C, 74.52, H, 6.13, N, 10.82.

Example 53

6-[3,5-Bis(trifluoromethyl)benzyl]-9-ethyl-5,6,7,8,9,10-hexahydro-3-methyl-5,10-dioxo-4-phenylpyrido[2,3-f][1,4]diazocine

N-[3,5-Bis(trifluoromethyl)benzyl]-2-ethylaminocarbonyl-N-(2-hydroxyethyl)-5-methyl-4-phenyl-3-pyridinecarboxamide(this was prepared by reacting the compound as obtained in Step 3 inReference Example 33 with ethylamine and treated in the same manner asin Step 4 in Reference Example 33) was reacted and treated in the samemanner as in Example 50 to obtain the entitled compound as colorlesscrystals. m.p. 228-229° C. (recrystallized from ethyl acetate-isopropylether) NMR(200 MHz, CDCl₃) ppm: 1.33(3H,t,J=7.0 Hz), 1.51(1H,dd,J=15,7.6Hz), 2.18(3H,s), 2.72(1H,m), 3.39(1H,m), 3.42(1H,d,J=14 Hz),3.57(1H,d,J=14 Hz), 3.57(1H,m), 3.77(1H,m), 4.03(1H,dd,J=15,7.6 Hz),7.2-7.6(5H,m), 7.48(2H,s), 7.74(1H,s), 8.69(1H,s) Elemental Analysis forC₂₇ H₂₃ N₃ O₂ F₆ : Calcd.(%): C, 60.56, H, 4.33, N, 7.85. Found (%): C,60.28, H, 4.51, N, 7.65.

Example 54

6-[3,5-Bis(trifluoromethyl)benzyl]-6,7,8,9,10,11-hexahydro-3,10-dimethyl-5,11-dioxo-4-phenyl-5H-pyrido[2,3-g][1,5]diazonine

The compound as obtained in Reference Example 36 was reacted and treatedin the same manner as in Example 50, to obtain the entitled compound ascolorless crystals. m.p. 247-249° C. (recrystallized from THF-ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 1.2-1.4(1H,m),1.8-2.3(1H,m), 2.15(3H,s), 3.0-3.6(4H,m), 3.04(3H,s), 3.91(1H,d,J=15Hz), 5.32(1H,d,J=15 Hz), 7.0-7.5(7H,m), 7.75(1H,s), 8.59(1H,s) ElementalAnalysis for C₂₇ H₂₃ N₃ O₂ F₆ : Calcd.(%): C, 60.56, H, 4.33, N, 7.85.Found (%): C, 60.41, H, 4.46, N, 7.87. EI-MS m/z: 535 (M⁺) [(C₂₇ H₂₃ N₃O₂ F₆)⁺ ]

Example 55

4-[3,5-Bis(trifluoromethyl)benzyl]-8-hydroxymethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

A mixture of8-acetoxymethyl-4-[3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine(Example 37) (4.51 g), ethanol (50 ml), and 4N-NaOH (50 ml) was stirredfor 1.5 hours at room temperature. After evaporation of the solvent,water was added to the residue. The pH of the mixture was adjusted toca.8 using dilute hydrochloric acid, and extracted with ethyl acetate.The extract was washed with water, dried and evaporated to give theentitled compound as colorless crystals (4.10 g). m.p. 199-201° C.(recrystallized from ethyl acetate-isopropyl ether) NMR(200 MHz, CDCl₃)ppm: 3.10(1H,b), 3.71(2H,t,J=5.6 Hz), 4.50(2H,t,J=5.6 Hz), 4.78(2H,s),4.88(2H,s), 7.20-7.50(6H,m), 7.80(2H,m), 7.87(1H,s).

Example 56

4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine-8-carboxylicacid

A mixture of4-[3,5-bis(trifluoromethyl)benzyl]-8-hydroxymethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine(Example 55) (3.49 g), 2N-NaOH (100 ml) and pottasium permanganate (2.22g) was stirred for 45 hours at room temperature. To the reaction mixturewas added saturated aqueous sodium thiosulfate (10 ml). After the pH ofthe mixture was adjusted to ca.3 using hydrochloric acid. The mixturewas extracted with ethyl acetate-THF (1:2). The extract was washed withaqueous sodium chloride solution, dried and evaporated to give theentitled compound as colorless crystals (2.74 g). m.p. 119-123° C.(recrystallized from methanol-ethyl ether) NMR(200 MHz, DMSO-d₆) ppm:3.94(2H,b), 4.46(2H,b), 4.91(2H,s), 7.25-7.55(5H,m), 7.90(1H,s),8.06(2H,s), 8.12(1H,s).

Example 57

4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine-8-carboxamide

A mixture of4-[3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine-8-carboxylicacid (Example 56) (220 mg), THF (15 ml), DMF (catalytic amount) andthionyl chloride (0.087 ml) was stirred for 2.5 hours with heating underreflux. The solvent was evaporated, and the residue was dissolved in THF(10 ml). To the solution was added aqueous ammonia (2 ml). After beingstirred for 1 hour at room temperature, the mixture was concentrated. Tothe concentrate was added water, and the mixture was extracted withethyl acetate. The extract was washed with water, dried and evaporatedto give the entitled compound as colorless crystals (163 mg). m.p.221-222° C. (recrystallized from ethyl acetate-isopropyl ether) NMR(200MHz, CDCl₃) ppm: 3.74(2H,t,J=5.6 Hz), 4.50(2H,t,J=5.6 Hz), 4.92(2H,s),5.80(1H,b), 7.30-7.55(6H,m), 7.83(2H,s), 7.89(1H,s), 8.20(1H,s).

The compounds of Examples 58 to 63 were similarly prepared by reactionand work-up as described in Example 57 using4-[3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine-8-carboxylicacid (Example 56) (via the acid chloride) and substituted amines(methylamine, dimethylamine, n-butylamine, piperidine, morpholine, and1-methylpiperazine). The physico-chemical data are described below.

Example 58

4-[3,5-Bis(trifluoromethyl)benzyl]-N-methyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine-8-carboxamide

m.p. 145° C. (decomposed) (recrystallized from THF-ethyl ether) NMR(200MHz, CDCl₃) ppm: 3.04(3H,d,J=5.2 Hz), 3.73(2H,t,J=5.4 Hz),4.48(2H,t,J=5.4 Hz), 4.90(2H,s), 7.25-7.60(5H,m), 7.65-7.95(1H,b),7.81(2H,s), 7.87(1H,s), 8.17(1H,s).

Example 59

4-[3,5-Bis(trifluoromethyl)benzyl]-N,N-dimethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine-8-carboxamide

m.p. 235-236° C. (recrystallized from ethyl acetate-isopropyl ether)NMR(200 MHz, CDCl₃) ppm: 3.11(3H,s), 3.15(3H,s), 3.72(2H,t,J=5.6 Hz),4.47(2H,t,J=5.6 Hz), 4.90(2H,s), 7.25-7.50(5H,m), 7.60(1H,s),7.82(2H,s), 7.88(1H,s).

Example 60

4-[3,5-Bis(trifluoromethyl)benzyl]-N-n-butyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f)[1,4]oxazepine-8-carboxamide

m.p. 194-196° C. (recrystallized from ethyl acetate-isopropyl ether)NMR(200 MHz, CDCl₃) ppm: 0.96(3H,t,J=7.2 Hz), 1.20-1.80(6H,m),4.78(2H,m), 3.73(2H,t,J=5.6 Hz), 4.49(2H,t,J=5.6 Hz), 4.91(2H,s),7.30-7.58(5H,m), 7.82(2H,s), 7.88(1H,s), 8.18(1H,s).

Example 61

4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenyl-8-piperidinocarbonylpyrido[3,2-f][1,4]oxazepine

m.p. 218-220° C. (recrystallized from THF-isopropyl ether) NMR(200 MHz,CDCl₃) ppm: 1.60(2H,b), 1.69(4H,b), 3.44(2H,t,J=5.6 Hz), 3.72(4H,m),4.46(2H,t,J=5.6 Hz), 4.89(2H,s), 7.20-7.60(6H,m), 7.81(2H,s),7.87(1H,s).

Example 62

4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-morpholinocarbonyl-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

m.p. 265-266° C. (recrystallized from ethyl acetate-isopropyl ether)NMR(200 MHz, CDCl₃) ppm: 3.55-3.90(10H,m), 4.46(2H,t,J=5.6 Hz),4.89(2H,s), 7.25-7.52(5H,m), 7.59(1H,s), 7.81(2H,s), 7.88(1H,s).

Example 63

4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-[1-(4-methylpiperazinyl)carbonyl]-5-oxo-6-phenyl-pyrido(3,2-f][1,4]oxazepine-8-carboxamide

m.p. 196-198° C. (recrystallized from THF-isopropyl ether) NMR(200 MHz,CDCl₃) ppm: 2.35(3H,s), 2.45(2H,m), 2.54(2H,m), 3.61(2H,m),3.72(2H,t,J=5.6 Hz), 3.84(2H,m), 4.46(2H,t,J=5.6 Hz), 4.89(2H,s),7.25-7.50(5H,m), 7.54(1H,s), 7.81(2H,s), 7.88(1H,s).

The compounds as described in Example 64-72 were obtained as colorlesscrystals from the compounds of Reference Example 37-45, respectively, bysubstantially the same reaction and work-up as Example 11 (i.e., bycyclization in the presence of sodium hydride in THF). Thephysico-chemical data are described below.

Example 64

2,3,4,5-Tetrahydro-5-oxo-6-phenyl-4-(3,4,5-trimethoxybenzyl)pyrido[3,2-f][1,4]oxazepine

m.p. 177-179° C. (recrystallized from acetone-ethyl ether) NMR(200 MHz,CDCl₃) ppm: 3.70(2H,t,J=5.6 Hz), 3.85(6H,s), 3.87(3H,s), 4.34(2H,t,J=5.6Hz), 4.72(2H,s), 6.60(2H,s), 7.24(1H,d,J=5.2 Hz), 7.30-7.55(5H,m),8.42(1H,d,J=5.2 Hz).

Example 65

4-(3,4-Dichlorobenzyl)-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

m.p. 189-192° C. (recrystallized from THF-ethyl ether) NMR(200 MHz,CDCl₃) ppm: 3.67(2H,t,J=5.4 Hz), 4.42(2H,t,J=5.4 Hz), 4.71(2H,s),7.10-7.70(9H,m), 8.43(1H,d,J=5.2 Hz).

Example 66

4-(3,4-Dimethoxybenzyl)-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

m.p. 175-176° C. (recrystallized from THF-ethyl ether) NMR(200 MHz,CDCl₃) ppm: 3.67(2H,t,J=5.4 Hz), 3.85(3H,s), 3.91(3H,s), 4.29(2H,t,J=5.4Hz), 4.72(2H,s), 6.80-7.00(3H,m), 7.22(1H,d,J=5.2 Hz), 7.30-7.50(5H,m),8.40(1H,d,J=5.2 Hz).

Example 67

4-Benzyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine

m.p. 209-211° C. (recrystallized from methanol-ethyl ether) NMR(200 MHz,CDCl₃) ppm: 3.64(2H,t,J=5.6 Hz), 4.33(2H,t,J=5.6 Hz), 4.77(2H,s),7.22(1H,d,J=5.2 Hz), 7.30-7.55(5H,m), 8.39(1H,d,J=5.2 Hz).

Example 68

2,3,4,5-Tetrahydro-6-oxo-7-phenyl-5-(3,4,5-trimethoxybenzyl)-6H-pyrido[2,3-b][1,5]oxazocine

m.p. 155-156° C. (recrystallized from ethyl acetate-ethyl ether) NMR(200MHz, CDCl₃) ppm: 1.65-1.85(1H,m), 2.29(1H,m), 3.40-3.75(2H,m),3.77(6H,s), 3.87(3H,s), 4.07(1H,d,J=14.2 Hz), 4.27(1H,m), 4.66(1H,m),5.22(1H,d,J=14.2 Hz), 6.53(2H,s), 7.15(1H,d,J=5.2 Hz), 7.35(5H,m),8.40(1H,d,J=5.2 Hz).

Example 69

(S)-5-Benzyl-2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine

m.p. 139-141° C. (recrystallized from ethyl acetate-isopropyl ether)NMR(200 MHz, CDCl₃) ppm: 0.84(3H,d,J=7.0 Hz), 2.43(1H,m),3.12(1H,d,J=14.8 Hz), 3.39(1H,dd,J=15.4&10.2 Hz), 3.72-4.00(2H,m),4.60(1H,dd,J=12.4&5.2 Hz), 5.51(1H,d,J=14.8 Hz), 7.16(1H,d,J=5.0 Hz),7.20-7.50(10H,m), 8.39(1H,d,J=5.0 Hz).

Example 70

(R)-5-Benzyl-2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine

m.p. 139-140° C. (recrystallized from ethyl acetate-isopropyl ether)NMR(200 MHz, CDCl₃) ppm: the same as the spectrum of the compound ofExample 69.

Example 71

(S)-5-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine

m.p. 142-143° C. (recrystallized from ethyl acetate-isopropyl ether)NMR(200 MHz, CDCl₃) ppm: 0.87(3H,d,J=7.0 Hz), 2.46(1H,m),3.10(1H,d,J=15.4 Hz), 3.59(1H,dd,J=15.0&10.6 Hz), 3.92(1H,dd,J=12.6&10.4Hz), 4.20(1H,d,J=15.4 Hz), 4.63(1H,dd,J=12.6&5.2 Hz), 5.50(1H,d,J=15.4Hz), 7.18(1H,d,J=5.0 Hz), 7.20-7.50(5H,m), 7.72(2H,s), 7.84(1H,s),8.43(1H,d,J=5.0 Hz).

Example 72

(R)-5-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H-pyrido[2,3-b)[1,5]oxazocine

m.p. 142-143° C. (recrystallized from ethyl acetate-isopropyl ether)NMR(200 MHz, CDCl₃) ppm: same as the spectrum of the compound of Example71.

Example 73

7-Benzyl-6,7,8,9,10,11-hexahydro-5-(4-methylphenyl)-6,13-dioxo-13H-[1,4]diazocino[2,1-g)[1,7]naphthyridine

The compound as obtained in Reference Example 46 was reacted and treatedin the same manner as Example 15. m.p. 239-241° C. (recrystallized fromethyl acetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 1.6-2.1(4H,m),2.50(3H,s), 3.14(1H,dd,J=15&3.8 Hz), 3.3-3.7(2H,m), 3.77(1H,d,J=15 Hz),5.14(1H,dd,J=14&5.9 Hz), 5.42(1H,d,J=15 Hz), 6.67(2H,d,J=7.0 Hz),6.92(1H,dd,J=7.6&1.8 Hz), 7.1-7.5(6H,m), 7.46(1H,dd,J=8.4&4.4 Hz),7.60(1H,dd,J=8.4&1.8 Hz), 8.90(1H,dd,J=4.4&1.8 Hz).

Example 74

(9R)-7-Benzyl-6,7,8,9,10,11-hexahydro-9-methyl-5-(4-methylphenyl)-6,13-dioxo-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 47 was reacted and treatedin the same manner as Example 15. m.p. 218-220° C. (recrystallized fromethyl acetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 0.85(3H,d,J=7.0Hz), 1.50-1.75(1H,m), 1.90-2.35(2H,m), 2.50(3H,s), 2.89(1H,d,J=15 Hz),3.26(1H,dd,J=14&10 Hz), 3.59(1H,dd,J=14&11 Hz), 3.75(1H,d,J=15 Hz),5.10(1H,dd,J=14&6.1 Hz), 5.42(1H,d,J=15 Hz), 6.69(2H,d,J=6.8 Hz),6.91(1H,dd,J=7.8&1.8 Hz), 7.1-7.5(6H,m), 7.46(1H,dd,J=8.4&4.2 Hz),7.60(1H,dd,J=8.4&1.8 Hz), 8.90(1H,dd,J=4.2&1.8 Hz).

Example 75

(9S)-7-Benzyl-6,7,8,9,10,11-hexahydro-9-methyl-5-(4-methylphenyl)-6,13-dioxo-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 48 was reacted and treatedin the same manner as Example 15. m.p. 218-220° C. (recrystallized fromethyl acetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: same as thespectrum of the compound of Example 74.

Example 76

(9R)-6,7,8,9,10,11-Hexahydro-9-methyl-5-(4-methylphenyl)-6,13-dioxo-7-(3,4,5-trimethoxybenzyl)-13H-[1,4]diazocino[2,1-g)[1,7]naphthyridine

The compound as obtained in Reference Example 49 was reacted and treatedin the same manner as Example 15. A white powder. NMR(200 MHz, CDCl₃)ppm: 0.90(3H,d,J=6.6 Hz), 1.5-1.8(1H,m), 1.9-2.5(2H,m), 2.41(3H,s),3.11(1H,d,J=15 Hz), 3.35(1H,dd,J=15&11 Hz), 3.56(1H,dd,J=14&11 Hz),3.7-3.9(1H,m), 3.75(6H,s), 3.87(3H,s), 5.07(1H,dd,J=14&5.9 Hz),5.19(1H,d,J=15 Hz), 6.30(2H,s), 6.77(1H,d,J=8.0 Hz), 6.97(1H,d,J=8.0Hz), 7.29(1H,d,J=8.2 Hz), 7.37(1H,d,J=8.2 Hz), 7.45(1H,dd,J=8.4&4.0 Hz),7.58(1H,dd,J=8.4&1.4 Hz), 8.89(1H,dd,J=4.0&1.4 Hz).

Example 77

(9S)-6,7,8,9,10,11-Hexahydro-9-methyl-5-(4-methylphenyl)-6,13-dioxo-7-(3,4,5-trimethoxybenzyl)-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 50 was reacted and treatedin the same manner as Example 15. A white powder. NMR(200 MHz, CDCl₃)ppm: same as the spectrum of the compound of Example 76.

Example 78

(9R)-7-(3,5-Dimethoxybenzyl)-6,7,8,9,10,11-hexahydro-9-methyl-5-(4-methylphenyl)-6,13-dioxo-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine

The compound as obtained in Reference Example 51 was reacted and treatedin the same manner as Example 15. m.p. 206-208° C. (recrystallized fromethanol-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 0.87(3H,d,J=7.0 Hz),1.67(1H,m), 1.9-2.4(2H,m), 2.42(3H,s), 3.05(1H,d,J=15 Hz),3.24-3.40(1H,m), 3.45-3.85(2H,m), 3.74(6H,s), 5.08(1H,dd,J=14&5.8 Hz),5.26(1H,d,J=14 Hz), 6.12(2H,d,J=2.0 Hz), 6.38(1H,t,J=2.0 Hz),6.84(1H,d,J=7.0 Hz), 7.09(1H,d,J=7.0 Hz), 7.29(1H,d,J=9.2 Hz),7.38(1H,d,J=9.2 Hz), 7.46(1H,dd,J=8.2&4.2 Hz), 7.62(1H,dd,J=8.2&1.6 Hz),8.89(1H,dd,J=4.2&1.6 Hz).

The compounds as described in Reference Example 37-45 were obtained aspale yellow oily substances using 2-chloro-4-phenyl-3-pyridinecarboxylicacid and N-substituted-N-(substituted)benzylamines-{i.e.,N-(2-hydroxyethyl)-N-(3,4,5-trimethoxybenzyl)amine,N-(3,4-dichlorobenzyl)-N-(2-hydroxyethyl)amine,N-(3,4-dimethoxybenzyl)-N-(2-hydroxyethyl)amine,N-benzyl-N-(2-hydroxyethyl)amine,N-(3-hydroxypropyl)-N-(3,4,5-trimethoxybenzyl)amine,N-benzyl-N-[(S)-3-hydroxy-2-methylpropyl)amine,N-benzyl-N-[(R)-3-hydroxy-2-methylpropyl]amine,N-[3,5-Bis(trifluoromethyl)benzyl]-N-[(S)-3-hydroxy-2-methylpropyl]amine,andN-[3,5-bis(trifluoromethyl)benzyl]-N-[(R)-3-hydroxy-2-methylpropyl]amine,respectively} by substantially the same reaction and work-up asReference Example 12--Step 2. The physico-chemical data are describedbelow.

The compounds as described in Example 79-82 were obtained as colorlesscrystals from the compounds of Reference Example 52-55, respectively, bysubstantially the same reaction and work-up as Example 11 (i.e., bycyclization in the presence of sodium hydride in THF). Thephysico-chemical data are described below.

Example 79

4-Benzyl-2,3,4,5-tetrahydro-5-oxo-6-(4-methylphenyl)pyrido[3,2-f][1,4]oxazepine

m.p. 203-204° C. (recrystallized from methanol-ethyl ether) NMR(200 MHz,CDCl₃) ppm: 2.41(3H,s), 3.64(2H,t,J=5.4 Hz), 4.32(2H,t,J=5.4 Hz),4.78(2H,s), 7.21 (1H,d,J=5.2 Hz), 7.25(4H,s), 7.38(5H,s),8.37(1H,d,J=5.2 Hz).

Example 80

4-[3,5-Bis(trifluoromethyl)benzyl]2,3,4,5-tetrahydro-5-oxo-6-(4-methylphenyl)pyrido[3,2-f][1,4]oxazepine

m.p. 212-213° C. (recrystallized from acetone-isopropyl ether) NMR(200MHz, CDCl₃) ppm: 2.40(3H,s), 3.70(2H,t,J=5.6 Hz), 4.47(2H,t,J=5.6 Hz),4.89(2H,s), 7.24(total 5H,m), 7.81 (2H,s), 7.87(1H,s), 8.41(1H,d,J=5.2Hz).

Example 81

(S)-5-Benzyl-2,3,4,5-tetrahydro-3-methyl-7-(4-methylphenyl)-6-oxo-6H-pyrido(2,3-b][1,5]oxazocine

m.p. 148-149° C. (recrystallized from acetone-ethyl ether) NMR(200 MHz,CDCl₃) ppm: 0.83(3H,d,J=7.4 Hz), 2.30-2.60(1H,b), 2.42(3H,s),3.11(1H,d,J=15.4 Hz), 3.40(1H,dd,J=15.4,10.4 Hz), 3.75-4.00(2H,m),4.59(1H,dd,J=12.4,4.8 Hz), 5.50(1H,d,J=15.0 Hz), 7.15(1H,d,J=4.8 Hz),7.20-7.40(total 9H,m), 8.37(11H,d,J=4.8 Hz).

Example 82

(S)-5-[3,5-Bis(trifluoromethyl)benzyl]2,3,4,5-tetrahydro-3-methyl-7-(4-methylphenyl)-6-oxo-6H-pyrido[2,3-b][1,5]oxazocine

m.p. 159-160° C. (recrystallized from acetone-isopropyl ether) NMR(200MHz, CDCl₃) ppm: 0.86(3H,d,J=7.0 Hz), 2.20-2.60(1H,b), 2.37(3H,s),3.09(1H,d,J=15.4 Hz), 3.58(1H,dd,J=15.4,10.4 Hz), 3.89(1H,t,J=11.6 Hz),4.18(1H,d,J=15.4 Hz), 4.62(1H,dd,J=12.2,5.2 Hz), 5.53(1H,d,J=15.4 Hz),7.17(total 5H,m), 7.72(2H,s), 7.84(1H,s), 8.40(1H,d,J=5.2 Hz).

Reference Example 1

N-[3,5-Bis(trifluoromethyl)benzyl]-7,8-dihydro-7-(2-hydroxyethyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

Step 1

Iodine (catalytic amount) was added to a THF (30 ml) suspension ofmagnesium (2.4 g) in a nitrogen atmosphere at room temperature withstirring, and then a THF (20 ml) solution of 4-bromotoluene (17.1 g) wasdropwise added thereto and stirred for 1 hour. The resulting mixture wasadded to a THF (50 ml) solution of 2,3-pyridinedicarboxylic acidanhydride (12.7 g) at 0-5° C. with stirring, and this was stirred foradditional 30 minutes as it was and then for 1 hour at room temperature.The solvent was removed from the reaction mixture by distillation, andwater (30 ml) was added to the residue, which was then adjusted the pHto 1.0 with hydrochloric acid. The mixture was extracted withdichloromethane, washed with water and dried. Then, the solvent wasremoved by distillation. Dichloromethane (about 10 ml) was added to theresidue, and then isopropyl ether (about 70 ml) was added thereto. Thiswas stirred for 16 hours at room temperature, and3-(4-methylbenzoyl)-2-pyridinecarboxylic acid was obtained as colorlesscrystals (5.0 g). m.p. 168-170° C. (recrystallized fromdichloromethane-ethyl acetate) NMR(200 MHz, CDCl₃) ppm: 2.41(3H,s),7.24(2H,d,J=8.4 Hz), 7.62(2H,d,J=8.4 Hz), 7.70(1H,dd,J=8.0,4.8 Hz),7.85(1H,dd,J=8.0,1.5 Hz), 8.77(1H,dd,J=4.8,1.5 Hz).

Step 2

A mixture of the compound (6.0 g) as obtained in Step 1, DMF (catalyticamount), thionyl chloride (10 ml), THF (50 ml) and dichloroethane (50ml) was refluxed for 3 hours. After the solvent was removed bydistillation, the residue was dissolved in dichloromethane (100 ml).Iminodiacetonitrile (3.0 g) and triethylamine (10 ml) were added to theresulting solution and stirred for 16 hours at room temperature. Then,the reaction mixture was washed with water, diluted hydrochloric acid,aqueous sodium hydrogencarbonate and water in that order, and dried.After the solvent was removed by distillation, obtained wasN,N-bis(cyanomethyl)-3-(4-methylbenzoyl)-2-pyridinecarboxamide as palebrown crystals (4.3 g). m.p. 166-168° C. (recrystallized from ethylacetate-ethyl ether) NMR(200 MHz, CDCl₃) ppm: 2.44(3H,s), 4.55(2H,s),4.69(2H,s), 7.31(2H,d,J=8.1 Hz), 7.56(1H,dd,J=7.9,4.9 Hz),7.69(2H,d,J=8.1 Hz), 7.94(1H,dd,J=7.9,1.6 Hz), 8.78(1H,dd,J=4.9,1.6 Hz)Elemental Analysis for C₁₈ H₁₄ N₄ O₂ : Calcd.(%): C, 67.92; H, 4.43; N,17.60. Found (%): C, 67.76; H, 4.54; N, 17.62.

Step 3

A mixture of the compound (0.86 g) as obtained in Step 2,1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (1 ml) and toluene (40 ml) washeated under reflux for 1 hour. The reaction mixture was diluted withethyl acetate, then washed with water, diluted hydrochloric acid,aqueous sodium hydrogencarbonate and water in that order, and dried.After the solvent was removed by distillation, obtained was7-cyanomethyl-7,8-dihydro-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarbonitrileas pale brown crystals (765 mg). m.p. 229-231° C. (recrystallized fromethyl acetate) NMR(200 MHz, CDCl₃) ppm: 2.48(3H,s), 5.28(2H,s),7.31(2H,d,J=8.2 Hz), 7.40(2H,d,J=8.2 Hz), 7.64(1H,dd,J=8.2,4.4 Hz),7.80(1H,dd,J=8.2,1.4 Hz), 9.06(1H,dd,J=4.4,1.4 Hz) Elemental Analysisfor C₁₈ H₁₂ N₄ O.0.2H₂ O: Calcd.(%): C, 71.14; H, 4.11; N, 18.43. Found(%): C, 71.20; H, 4.26; N, 18.20.

Step 4

A mixture of the compound (2.35 g) as obtained in Step 3, hydrochloricacid (25 ml) and acetic acid (25 ml) was heated under reflux for 1.5hours. After the solvent was removed by distillation, water was added tothe residue, and the resulting mixture was extracted with ethyl acetate.The resulting extract was washed with a saturated saline solution andthen dried. After solvent was removed by distillation, obtained was7-carboxymethyl-7,8-dihydro-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarbonitrileas colorless crystals (1.62 g). m.p. 253-254° C. (recrystallized fromethyl acetate) NMR(200 MHz, CDCl₃) ppm: 2.46(3H,s), 5.22(2H,s),6.64(1H,bs,--CO₂ H), 7.32(2H,d,J=8.2 Hz), 7.37(2H,d,J=8.2 Hz),7.62(1H,dd,J=8.4,4.4 Hz), 7.82(1H,d,J=8.4 Hz), 9.09(1H,d,J=4.4 Hz)Elemental Analysis for C₁₈ H₁₃ N₃ O₃ 0.1H₂ O: Calcd.(%): C, 67.33; H,4.14; N, 13.09. Found (%): C, 67.28; H, 4.19; N, 13.00.

Step 5

Hydroxybenzotriazole (770 mg) and 1,3-dicyclohexylcarbodiimide (1.23 g)were added to a THF (50 ml) solution of the compound (1.54 g) asobtained in Step 4, and stirred for 3 hours at room temperature. Next,sodium borohydride (550 mg) was added to the reaction mixture andstirred for 20 minutes at room temperature. The resulting reactionmixture was diluted with ethyl acetate, then washed with water anddried, and the solvent was removed by distillation. Dichloromethane wasadded to the residue, the insoluble substances were removed byfiltration, and the solvent was removed by distillation. Hydrochloricacid (50 ml) was added to the residue and heated under reflux for 16hours. The solvent was removed by distillation, and water with ice wasadded to the residue. Then, this was made alkaline with aqueouspotassium carbonate, and thereafter extracted with ethyl acetate. Theextract was washed with water and dried, and the solvent was removed bydistillation. Thus, obtained was6,8,9,11-tetrahydro-5-(4-methylphenyl)-6,11-dioxo[1,4]oxazino[3,4-g)[1,7]naphthyridineas colorless crystals (0.86 g). m.p. 247-249° C. (recrystallized fromethyl acetate) NMR(200 MHz, CDCl₃) ppm: 2.45(3H,s), 4.48-4.72(4H,m),7.12(2H,d,J=8.0 Hz), 7.32(2H,d,J=8.0 Hz), 7.55(1H,dd,J=8.4,4.4 Hz),7.68(1H,dd,J=8.4,1.6 Hz), 9.01(1H,dd,J=4.4,1.6 Hz) Elemental Analysisfor Cl₈ H₁₄ N₂ O₃ 0.2H₂ O: Calcd.(%): C, 69.76; H, 4.68; N, 9.04. Found(%): C, 69.64; H, 4.86; N, 8.95.

Step 6

A mixture of the compound (410 mg) as obtained in Step 5 and3,5-bis(trifluoromethyl)benzylamine (1.2 g) was heated in an argonatmosphere at 150° C. for 2.5 hours. After this was cooled to roomtemperature, isopropyl ether was added thereto and the entitled compoundwas obtained as colorless crystals (441 mg). m.p. 123-125° C.(recrystallized from ethyl acetate) NMR(200 MHz, CDCl₃) ppm: 2.28(3H,s),3.71(2H,m), 3.97(2H,m), 4.46(2H,d,J=5.2 Hz), 7.00-7.20(4H,m),7.37(1H,dd,J=8.4,4.2 Hz), 7.52(1H,dd,J=8.4,1.6 Hz), 7.66(2H,s),7.76(1H,s), 8.51(1H,bs), 8.61(1H,dd,J=4.2,1.6 Hz) Elemental Analysis forC₂₇ H₂₁ N₃ O₃ F₆ : Calcd.(%): C, 59.02; H, 3.85; N, 7.65. Found (%): C,58.95; H, 3.95; N, 7.52.

Reference Example 2

N-[3,5-Bis(trifluoromethyl)benzyl]-7-(3-chloropropyl)-7,8-dihydro-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

Step 1

A mixture of 3-(4-methylbenzoyl)-2-pyridinecarboxylic acid (13.9 g),diethyl bromomalonate (15.4 g), triethylamine (9.1 ml) and THF (120 ml)was heated under reflux for 6 hours. The solvent was removed bydistillation, and ethyl acetate was added to the residue, which waswashed with water, diluted hydrochloric acid and a saturated salinesolution in that order and then dried. After the solvent was removed bydistillation, the oily residue (20.5 g) was dissolved in THF (120 ml).DBU (4.2 ml) was added to the solution at -78° C. The mixture wasstirred at 0° C. for 15 minutes, and then the solvent was concentrated.The resulting concentrate was poured into 2 N-HCl and then adjusted thepH to about 10 with sodium hydrogencarbonate. Then, this was extractedwith ethyl acetate. The extract was washed with water and dried, andthen the solvent was removed by distillation. Thus, obtained was diethyl5,6-dihydro-5-hydroxy-5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6,6-dicarboxylate as colorless crystals (14.1 g). m.p.148-149° C. (recrystallized from ethyl acetate-isopropyl ether) NMR(200MHz, CDCl₃) ppm: 1.06(3H,t,J=7.1 Hz), 1.21(3H,t,J=7.1 Hz), 2.31(3H,s),3.95-4.30(4H,m), 4.65(1H,s), 7.15(2H,d,J=8.3 Hz), 7.55(1H,dd,J=8.0,4.8Hz), 7.65(2H,d,J=8.3 Hz), 8.47(1H,dd,J=8.0,1.4 Hz), 8.86(1H,dd,J=4.8,1.4Hz) Elemental Analysis for C₂₁ H₂₁ NO₇ : Calcd.(%): C, 63.15; H, 5.30;N, 3.51. Found (%): C, 63.09; H, 5.16; N, 3.47.

The same compound was alternatively obtained by the method describedbelow.

A mixture of 3-(4-methylbenzoyl)-2-pyridinecarboxylic acid (3.0 g), DMF(1 drop), thionyl chloride (4.5 ml) and THF (30 ml) was heated underreflux for 2 hours. The solvent was evaporated, and the crystallineresidue was dissolved in THF (50 ml). To the solution was added diethylhydroxymalonate (4.1 g), and then added portionwise sodium hydride (60%oily) (646 mg) with stirring and cooling at -10° C. After being stirredfor 30 minutes at -10° C., the reaction mixture was added to a solutionof ethyl acetate (100 ml)-water (100 ml). The organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Theorganic layer and the extract were combined, washed with water andaqueous sodium chloride solution, dried and evaporated to give the abovedescribed compound as colorless crystals (4.0 g).

Step 2

A mixture of the compound (14.1 g) as obtained in Step 1, acetic acid(100 ml) and hydrochloric acid (100 ml) was heated under reflux for 3hours. The solvent was removed by distillation, and water was added tothe residue. Thus, obtained was5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxylic acid ascolorless crystals (8.45 g). m.p. 274-277° C. (browned at about 240° C.)(recrystallized from THF-isopropyl ether) NMR(200 MHz, CDCl₃ -DMSO-d₆)ppm: 2.43(3H,s), 6.10(1H,bs,--CO₂ H), 7.16(2H,d,J=8.0 Hz),7.29(2H,d,J=8.0 Hz), 7.50-7.70(2H,m), 8.94(1H,m) Elemental Analysis forC₁₆ H₁₁ NO₄.10.1H₂ O: Calcd.(%): C, 67.89; H, 3.99; N, 4.95. Found (%):C, 67.70; H, 4.06; N, 4.83.

Step 3

A THF (5 ml) solution of5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxylic acid (150mg) was dropwise added to a mixture of 3-bromopropylamine hydrobromide(1.5 g), triethylamine (2.0 ml) and methanol (5 ml), and stirred at roomtemperature for 2 hours. Then, the solvent was removed by distillation.Hydrochloric acid (10 ml) was added to the residue, stirred for 14 hoursat room temperature and then concentrated. The resulting concentrate wasadjusted the pH to 1 with 1 N-NaOH. The crystals thus precipitated weretaken out by filtration and washed with water to obtain7-(3-bromopropyl)-7,8-dihydro-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxylicacid as colorless crystals (131 mg). m.p. 194-196° C. (recrystallizedfrom THF-isopropyl ether) NMR(200 MHz, CDCl₃ -DMSO-d₆) ppm:2.30-2.60(2H,m), 2.42(3H,s), 3.54(2H,t,J=6.8 Hz), 4.29(2H,t,J=7.2 Hz),5.42(1H,bs,--CO₂ H), 7.20-7.40(4H,m), 7.50(1H,m), 7.64(1H,d,J=8.0 Hz),8.88(1H,m).

Step 4

A mixture of the compound (110 mg) as obtained in Step 3, DMF (catalyticamount), thionyl chloride (0.3 ml), 1,2-dichloroethane (3 ml) and THF (3ml) was heated under reflux for 40 minutes, and then the solvent wasremoved by distillation. A mixture of THF (5 ml),3,5-bis(trifluoromethyl)benzylamine (82 mg), triethylamine (0.12 ml) andTHF (2 ml) was added to the residue and stirred for 2 hours at roomtemperature. Ethyl acetate was added to the reaction mixture, which waswashed with water, diluted hydrochloric acid, aqueous sodiumhydrogencarbonate and water in that order, and then dried. After thesolvent was removed by distillation, the entitled compound was obtainedas colorless crystals (79 mg). m.p. 22.7-229° C. (recrystallized fromethyl acetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 2.10-2.40(2H,m),2.27(3H,s), 3.4-3.7(4H,m), 4.49(2H,d,J=5.8 Hz), 7.07(2H,d,J=7.6 Hz),7.24(2H,d,J=7.6 Hz), 7.40(1H,dd,J=8.4,4.2 Hz), 7.54(1H,dd,J=8.4,1.4 Hz),7.67(2H,s), 7.78(1H,s), 8.06(1H,bt), 8.70(1H,dd,J=4.2,1.4 Hz) ElementalAnalysis for C₂₈ H₂₂ N₃ O₂ ClF₆.0.2H₂ O: Calcd.(%): C, 57.43; H, 3.86;N, 7.18. Found (%): C, 57.29; H, 3.98; N, 7.07.

Reference Example 3

N-[3,5-Bis(trifluoromethyl)benzyl]-5-(4-methylphenyl)-8-oxo-8H-pyrano(3,4-b]pyridine-6-carboxamide

The compound as obtained in Step 2 in Reference Example 2 was reactedwith 3,5-(bistrifluoromethyl)benzylamine and treated in the same manneras in Step 4 in Reference Example 2, to obtain the entitled compound ascolorless crystals. m.p. 182-183° C. (recrystallized from ethylacetate-ether) NMR(200 MHz, CDCl₃) ppm: 2.44(3H,s), 4.63(2H,d,J=6.4 Hz),7.17(2H,d,J=8.1 Hz), 7.34(2H,d,J=8.1 Hz), 7.50-7.65(3H,m), 7.73(2H,s),7.80(1H,s), 8.96(1H,m) Elemental Analysis for C₂₅ H₁₆ N₂ O₃ F₆ :Calcd.(%): C, 59.30; H, 3.18; N, 5.53. Found (%): C, 59.42; H, 3.30; N,5.45.

Reference Example 4

N-(2-methoxybenzyl)-5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxamide

The compound as obtained in Step 2 in Reference Example 2 was reactedwith 2-methoxybenzylamine and treated in the same manner as in Step 4 inReference Example 2, to obtain the entitled compound as colorlesscrystals. m.p. 189-190° C. (recrystallized from ethyl acetate) NMR(200MHz, CDCl₃) ppm: 2.44(3H,s), 3.90(3H,s), 4.48(2H,d,J=5.8 Hz),6.85-6.95(2H,m), 7.10-7.35(6H,m), 7.43(1H,bt), 7.50-7.63(2H,m),8.93(1H,m).

Reference Example 5

N-[3,5-Bis(trifluoromethyl)benzyl]-7,8-dihydro-7-(4-hydroxybutyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

4-Amino-1-butanol (0.5 ml) was added to a THF (5 ml)-methanol (10 ml)solution of the compound (200 mg) as obtained in Reference Example 3, at0° C., and stirred at room temperature for 1 hour. The solvent wasremoved from the reaction mixture by distillation, and hydrochloric acid(15 ml) was added to the residue and stirred for 14 hours at roomtemperature. The reaction mixture was poured into aqueous potassiumcarbonate with ice and then extracted with ethyl acetate. The extractwas washed with water and dried, and the solvent was removed bydistillation. Thus, the entitled compound was obtained as colorlesscrystals (144 mg). m.p. 187-188° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 1.3-1.5(2H,m),1.6-1.9(2H,m), 2.29(3H,s), 2.82(1H,bs), 3.55(2H,t,J=5.7 Hz), 3.69(2H,m),4.48(2H,d,J=5.8 Hz), 7.08(2H,d,J=8.1 Hz), 7.21(2H,d,J=8.1 Hz),7.29(1H,dd,J=8.4,4.2 Hz), 7.52(1H,dd,J=8.4,1.4 Hz), 7.68(2H,s),7.78(1H,s), 8.39(1H,bt), 8.61(1H,dd,J=4.2,1.4 Hz).

Reference Example 6

7,8-Dihydro-7-(3-hydroxypropyl)-N-(2-methoxybenzyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3.4-b]pyridinecarboxamide

The compound as obtained in Reference Example 4 was reacted with3-amino-1-propanol and treated in the same manner as in ReferenceExample 5, to obtain the entitled compound. This compound was used inExample 4 without being purified.

Reference Example 7

7,8-Dihydro-7-(4-hydroxybutyl)-N-(2-methoxybenzyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

The compound as obtained in Reference Example 4 was reacted with3-amino-1-butanol and treated in the same manner as in Reference Example5, to obtain the entitled compound as colorless crystals. m.p. 205-206°C. (recrystallized from methanol-ethyl ether) NMR(200 MHz, CDCl₃) ppm:1.57(2H,m), 1.95(2H,m), 2.33(3H,s), 2.71(1H,bs), 3.66(2H,t,J=6.0 Hz),3.75(3H,s), 4.00-4.15(2H,m), 4.29(2H,d,J=6.2 Hz), 6.59(1H,bt),6.71-6.92(3H,m), 7.04-7.30(5H,m), 7.41(1H,dd,J=8.4,4.4 Hz),7.62(1H,dd,J=8.4,1.4 Hz), 8.82(1H,dd,J=4.4,1.4 Hz).

Reference Example 8

N-[3,5-Bis(trifluoromethyl)benzyl]-7,8-dihydro-7-(5-hydroxypentyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

The compound as obtained in Reference Example 3 was reacted with5-amino-1-pentanol and treated in the same manner as in ReferenceExample 5, to obtain the entitled compound as colorless crystals. m.p.136-137° C. (recrystallized from ethyl acetate-ethyl ether) NMR(200 MHz,CDCl₃) ppm: 1.10-1.35(2H,m), 1.35-1.55(2H,m), 1.6-1.9(2H,m), 2.28(3H,s),3.50-3.70(4H,m), 4.47(2H,d,J=5.8 Hz), 7.06(2H,d,J=8.0 Hz),7.19(2H,d,J=8.0 Hz), 7.35(1H,dd,J=8.3,4.4 Hz), 7.50(1H,d,J=8.3,1.4 Hz),7.69(2H,s), 7.78(1H,s), 8.29(1H,bt), 8.64(1H,dd,J=4.4,1.4 Hz).

Reference Example 9

N-[3,5-Bis(trifluoromethyl)benzyl]-7,8-dihydro-7-(3-hydroxypropyl)-8-oxo-5-phenyl-6-pyrido[3,4-b]pyridinecarboxamide

Step 1

3-Benzoyl-2-pyridinecarboxylic acid was used in place of3-(4-methylbenzoyl)-2-pyridinecarboxylic acid in Step 1 in ReferenceExample 2, reacted and treated in the same manner as in Step 1 inReference Example 2, to obtain diethyl5,6-dihydro-5-hydroxy-8-oxo-5-phenyl-8H-pyrano[3,4-b]pyridine-6,6-dicarboxylateas colorless crystals. m.p. 146-147° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 1.07(3H,t,J=7.2 Hz),1.18(3H,t,J=7.2 Hz), 4.00-4.25(4H,m), 4.70(1H,s), 7.30-7.40(3H,m),7.56(1H,dd,J=8.0,4.8 Hz), 7.74-7.85(2H,m), 8.48(1H,dd,J=8.0,1.5 Hz),8.87(1H,dd,J=4.8,1.5 Hz).

Step 2

The compound as obtained in Step 1 was reacted with acetic acid andhydrochloric acid and treated in the same manner as in Step 2 inReference Example 2, to obtain8-oxo-5-phenyl-8H-pyrano[3,4-b]pyridine-6-carboxylic acid as colorlesscrystals. m.p. 288-290° C. (recrystallized from THF-methanol-ether)NMR(200 MHz, DMSO-d₆) ppm: 7.28-7.60(6H,m), 7.81(1H,dd,J=8.2,4.4 Hz),8.95(1H,dd,J=4.4,1.6 Hz).

Step 3

The compound as obtained in Step 2 was reacted with3,5-bis(trifluoromethyl)benzylamine and treated in the same manner as inReference Example 3, to obtainN-[3,5-bis(trifluoromethyl)benzyl]1-8-oxo-5-phenyl-8H-pyrano[3,4-b]pyridine-6-carboxamide as colorless crystals. m.p. 182-183° C.(recrystallized from ethyl acetate-isopropyl ether) NMR(200 MHz, CDCl₃)ppm: 4.61(2H,t,J=6.2 Hz), 7.24-7.34(2H,m), 7.49-7.67(6H,m), 7.72(2H,s),7.79(1H,s), 8.96(1H,dd,J=4.2,1.6 Hz).

Step 4

The compound as obtained in Step 3 was reacted with 3-amino-1-propanoland treated in the same manner as in Reference Example 5, to obtain theentitled compound as colorless crystals. m.p. 129-130° C.(recrystallized from ethyl acetate-ethyl ether) NMR(200 MHz, CDCl₃) ppm:1.91(2H,m), 3.45(2H,t,J=5.4 Hz), 3.70(2H,m), 4.46(2H,d,J=6.0 Hz),7.2-7.4(5H,m), 7.44(1H,dd,J=8.4,4.4 Hz), 7.59(1H,dd,J=8.4,1.6 Hz),7.61(2H,s), 7.78(1H,s), 8.25(1H,bt), 8.70(1H,dd,J=4.4,1.6 Hz).

Reference Example 10

N-[3,5-Bis(trifluoromethyl)benzyl]-7,8-dihydro-7-(4-hydroxybutyl)-8-oxo-5-phenyl-6-pyrido[3,4-b]pyridinecarboxamide

The compound as obtained in Step 3 in Reference Example 9 was reactedwith 4-amino-1-butanol and treated in the same manner as in ReferenceExample 5, to obtain the entitled compound as colorless crystals. m.p.155-157° C. (recrystallized from ethyl acetate-isopropyl ether) NMR(200MHz, CDCl₃) ppm: 1.45(2H,m), 1.83(2H,m), 3.58(2H,t,J=5.8 Hz),3.73(2H,m), 4.44(2H,d,J=5.8 Hz), 7.2-7.4(6H,m), 7.54(1H,dd,J=8.1,1.1Hz), 7.60(2H,s), 7.77(1H,s), 8.05(1H,bt), 8.66(1H,dd,J=4.1,1.1 Hz).

Reference Example 11

N-[3,5-Bis(trifluoromethyl)benzyl]-1,2-dihydro-2-(4-hydroxybutyl)-4-(4-methylphenyl)-1-oxo-3-pyrido[3,4-c]pyridinecarboxamide

Step 1

4-(4-Methylbenzoyl)-3-pyridinecarboxylic acid was used in place of3-(4-methylbenzoyl)-2-pyridinecarboxylic acid in Step 1 in ReferenceExample 2, reacted and treated in the same manner as in Step 1 inReference Example 2, to obtain diethyl3,4-dihydro-4-hydroxy-4-(4-methylphenyl)-1-oxo-1H-pyrano[3,4-c]pyridine-3,3-dicarboxylateas an yellow oil. NMR(200 MHz, CDCl₃) ppm: 1.08(3H,t,J=7.1 Hz),1.21(3H,t,J=7.2 Hz), 2.31(3H,s), 4.00-4.40(4H,m), 4.72(1H,bs),7.14(2H,d,J=8.4 Hz), 7.64(2H,d,J=8.4 Hz), 8.05(1H,d,J=5.3 Hz),8.85(1H,d,J=5.3 Hz), 9.12(1H,s).

Step 2

The compound as obtained in Step 1 was reacted with acetic acid andhydrochloric acid and treated in the same manner as in Step 2 inReference Example 2, to obtain4-(4-methylphenyl)-1-oxo-1H-pyrano[3,4-c]pyridine-3-carboxylic acid ascolorless crystals. m.p. 254-256° C. (recrystallized from THF-isopropylether) NMR(200 MHz, CDCl₃ +d₆ -DMSO) ppm: 2.43(3H,s), 5.31(1H,bs,COOH),7.04(1H,d,J=5.5 Hz), 7.16(2H,d,J=7.8 Hz),, 7.29(2H,d,J=7.8 Hz),8.81(1H,d,J=5.5 Hz), 9.54(1H,s).

Step 3

The compound as obtained in Step 2 was reacted with3,5-bis(trifluoromethyl)benzylamine and treated in the same manner as inReference Example 3, to obtainN-[3,5-bis(trifluoromethyl)benzyl]-4-(4-methylphenyl)-1-oxo-1H-pyrano[3,4-c]pyridine-3-carboxamideas colorless crystals. m.p. 188-189° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 2.44(3H,s),4.61(2H,d,J=6.2 Hz), 7.05(1H,d,J=5.3 Hz), 7.15(2H,d,J=8.1 Hz),7.32(2H,d,J=8.1 Hz), 7.43(1H,bt), 7.70(2H,s), 7.80(1H,s),8.85(1H,d,J=5.3 Hz), 9.56(1H,s).

Step 4

The compound as obtained in Step 3 was reacted with 4-amino-1-butanoland treated in the same manner as in Reference Example 5, to obtain theentitled compound as colorless crystals. m.p. 128-131° C.(recrystallized from ethyl acetate-isopropyl ether) NMR(200 MHz, CDCl₃)ppm: 1.45-1.70(2H,m), 1.75-2.05(2H,m), 2.31(3H,s), 3.65(2H,t,J=5.9 Hz),3.98(2H,m), 4.36(2H,d,J=6.0 Hz), 7.00(1H,d,J=5.7 Hz), 7.12(2H,d,J=8.1Hz), 7.18(2H,d,J=8.1 Hz), 7.56(2H,s), 7.80(1H,s), 8.47(1H,d,J=5.7 Hz),9.41(1H,s).

Reference Example 12

N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-(2-hydroxyethyl)-4-phenyl-3-pyridinecarboxamide

Step 1

3,5-Bis(trifluoromethyl)benzyl bromide (1.1 ml) was added to a THF (30ml) solution of 2-aminoethanol (3.6 ml) while cooling it with ice. Theresulting mixture was stirred for 1 hour at room temperature, ethylacetate (30 ml) was added thereto, and this was washed with water and asaturated, aqueous sodium chloride solution. The organic layer was driedand the solvent was removed by distillation. Thus, obtained wasN-(3,5-bis(trifluoromethyl)benzyl]-N-(2-hydroxyethyl)amine as colorlesscrystals (1.38 g). m.p. 107-108° C. (recrystallized from ethanol-ethylether) NMR(200 MHz, CDCl₃) ppm: 2.83(2H,t,J=5.4 Hz), 3.72(2H,t,J=5.4Hz), 3.96(2H,s), 7.78(1H,s), 7.82(2H,s).

Step 2

Thionyl chloride (0.7 ml) and DMF (catalytic amount) were added to a THF(10 ml) solution of 2-chloro-4-phenyl-3-pyridinecarboxylic acid (318 mg)and heated under reflux for 4 hours. The solvent was removed bydistillation, and the residue was dissolved in THF (5 ml). The resultingsolution was added to a mixture ofN-[3,5-bis(trifluoromethyl)benzyl]-N-(2-hydroxyethyl)amine (391 mg) thathad been obtained in Step 1, triethylamine (0.57 ml) and THF (10 ml),while cooling with ice, and then stirred for 2 hours at roomtemperature. The solvent was removed by distillation, and water wasadded to the residue, which was then extracted with ethyl acetate. Theextract was washed with water and dried, and then the solvent wasremoved by distillation. The residue was separated and purified bycolumn chromatography (hexane:ethyl acetate=1:1) using silica gel, andthe entitled compound was obtained as an oil (551 mg) (ratio ofcis-trans isomers with respect to the amide bond=about 2:1). NMR(200MHz, CDCl₃) ppm: 2.82-3.92(4H,m), 4.16(1H×1/3,d,J=16.0 Hz),4.41(1H×1/3,d,J=16.0 Hz), 4.73(1H×2/3,d,J=15.0 Hz), 4.87(1H×2/3,d,J=15.0Hz), 7.20-8.85(9H,m), 8.43(1H,m).

Reference Example 13

(S)-N-[3,5-Bis(trifluoromethyl)benzyl]-7,8-dihydro-7-(3-hydroxy-2-methylpropyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

(S)-3-Amino-2-methyl-1-propanol (307 mg) was added to a THF (10ml)-methanol (7.5 ml) solution of the compound (1.0 g) as obtained inReference Example 3, and stirred for 14 hours at room temperature.Diluted hydrochloric acid was added to the reaction mixture, which wasthen extracted with ethyl acetate. The extract was washed with asaturated saline solution and then dried, and the solvent was removed bydistillation. Acetonitrile (3 ml), toluene (21 ml) and DBU (0.42 ml)were added to the residue and heated under reflux for 1 hour. Aftercooled, the reaction mixture was diluted with ethyl acetate and thenwashed with water, diluted hydrochloric acid and a saturated salinesolution in that order. The organic layer was dried, and the solvent wasremoved by distillation. Thus, the entitled compound was obtained ascolorless crystals. m.p. 123-125° C. (after once melted, this againsolidified), 215-216° C. (re-melted) (recrystallized from ethylacetate-isopropyl ether) [α]_(D) : +11.1° (C=0.350,CHCl₃) NMR(200 MHz,CDCl₃) ppm: 0.79(3H,d,J=7.0 Hz), 2.13(1H,m), 2.28(3H,s),3.10-3.70(4H,m), 4.48(2H,d,J=6.2 Hz), 7.00-7.25(4H,m),7.43(1H,dd,J=8.4,4.2 Hz), 7.59(1H,dd,J=8.4,1.6 Hz), 7.69(2H,s),7.79(1H,s), 8.38(1H,bt), 8.70(1H,dd,J=4.2,1.6 Hz) Elemental Analysis forC₂₉ H₂₅ N₃ O₃ F₆.0.5H₂ O: Calcd.(%): C, 59.39; H, 4.47; N, 7.16. Found(%): C, 59.64; H, 4.31; N, 7.01.

Reference Example 14

(R)-N-[3,5-Bis(trifluoromethyl)benzyl]-7,8-dihydro-7-(3-hydroxy-2-methylpropyl)-8-oxo-5-phenyl-6-pyrido[3,4-b]pyridinecarboxamide

The compound as obtained in Step 3 in Reference Example 9 was reactedwith (R)-3-amino-2-methyl-1-propanol and treated in the same manner asin Reference Example 13, to obtain the entitled compound as colorlesscrystals. m.p. 101-103° C. (recrystallized from ethyl ether-isopropylether) NMR(200 MHz, CDCl₃) ppm: 0.77(3H,d,J=6.6 Hz), 2.14(1H,m),3.10-3.70(4H,m), 4.47(2H,d,J=5.8 Hz), 7.1-7.4(5H,m),7.45(1H,dd,J=8.4,4.2 Hz), 7.60(1H,d,J=8.4 Hz), 7.65(2H,s), 7.78(1H,s),8.60(1H,bt), 8.69(1H,d,J=4.2 Hz) [α]_(D) : -5.4° (C=0.512,CHCl₃).

Reference Example 15

(R)-N-(3,5-Bis(trifluoromethyl)benzyl]-7,8-dihydro-7-(3-hydroxy-2-methylpropyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

The compound as obtained in Reference Example 3 was reacted with(R)-3-amino-2-methyl-1-propanol and treated in the same manner as inReference Example 13, to obtain the entitled compound as colorlesscrystals. m.p. 123-125° C. (after once melted, this again solidified),215-216° C. (re-melted) (recrystallized from ethyl acetate-isopropylether) NMR(200 MHz, CDCl₃) ppm: same as the spectrum of the compound ofReference Example 13. [α]_(D) : -9.0° (C=0.346,CHCl₃).

Reference Example 16

(+/-)-N-[3,5-Bis(trifluoromethyl)benzyl)-7,8-dihydro-7-(4-hydroxy-3-methylbutyl)-8-oxo-5-phenyl-6-pyrido[3,4-b]pyridinecarboxamide

The compound as obtained in Step 3 in Reference Example 9 was reactedwith 4-amino-2-methyl-1-butanol and treated in the same manner as inReference Example 13, to obtain the entitled compound as colorlesscrystals. m.p. 217-219° C. (recrystallized from ethyl acetate-isopropylether).

Reference Example 17

(+/-)-N-[3,5-Bis(trifluoromethyl)benzyl]-7,8-dihydro-7-(4-hydroxy-3-methylbutyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

The compound as obtained in Reference Example 3 was reacted with4-amino-2-methyl-1-butanol and treated in the same manner as inReference Example 13, to obtain the entitled compound as colorlesscrystals. m.p. 129-130° C. (after once melted, this again solidified),188-190° C. (re-melted) (recrystallized from ethyl acetate-isopropylether) NMR(200 MHz, CDCl₃) ppm: 0.79(3H,d,J=6.6 Hz), 1.4-1.8(3H,m),2.28(3H,s), 3.03(1H,t,J=6.6 Hz,--OH), 3.2-3.7(4H,m), 4.49(2H,d,J=5.8Hz), 7.0-7.3(4H,m), 7.30(1H,dd,J=8.4,4.4 Hz), 7.53(1H,dd,J=8.4,1.4 Hz),7.68(2H,s), 7.78(1H,s), 8.48(1H,t,J=6.0 Hz), 8.61(1H,dd,J=4.4,1.4 Hz).

Reference Example 18

(R)-N-[3,5-Bis(trifluoromethyl)benzyl]-7,8-dihydro-7-(4-hydroxy-3-methylbutyl)-8-oxo-5-phenyl-6-pyrido[3,4-b]pyridinecarboxamide

The compound as obtained in Step 4 in Reference Example 9 was reactedwith (R)-4-amino-2-methyl-1-butanol tetrahydropyranyl (THP) ether andtreated in the same manner as in Reference Example 13, to obtain THPether of the entitled compound as a pale orange oil. This compound wasreacted with p-toluenesulfonic acid in methanol at room temperature tothereby remove the THP group, and the entitled compound was obtained ascolorless crystals. m.p. 213-215° C. (recrystallized from ethylacetate-ethyl ether) NMR(200 MHz, CDCl₃) ppm: same as the spectrum ofthe compound of Reference Example 16. [α]_(D) : +1.0° (C=0.519,CHCl₃).

Reference Example 19

(R)-N-[3,5-Bis(trifluoromethyl)benzyl]-7,8-dihydro-7-(4-hydroxy-3-methylbutyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

The compound as obtained in Reference Example 3 was reacted with(R)-4-amino-2-methyl-1-butanol THP ether and treated in the same manneras in Reference Example 13, to obtain THP ether of the entitled compoundas a pale orange oil. This compound was reacted with p-toluenesulfonicacid in methanol at room temperature to thereby remove the THP group,and the entitled compound was obtained as colorless crystals. m.p.123-125° C. (after once melted, this again solidified), 205-206° C.(re-melted) (recrystallized from ethyl acetate-isopropyl ether) NMR(200MHz, CDCl₃) ppm: same as the spectrum of the compound of ReferenceExample 17. [α]_(D) : +1.2° (C=0.471,CHCl₃).

Reference Example 20

(S)-N-[3,5-Bis(trifluoromethyl)benzyl]-7,8-dihydro-7-(4-hydroxy-3-methylbutyl)-8-oxo-5-phenyl-6-pyrido[3,4-b]pyridinecarboxamide

(S)-4-Amino-2-methyl-1-butanol THP ether was used in place of(R)-4-amino-2-methyl-1-butanol THP ether in Reference Example 18 andreacted and treated in the same manner as in Reference Example 18, toobtain the entitled compound as colorless crystals. m.p. 213-214° C.(recrystallized from ethyl acetate-ethyl ether) NMR(200 MHz, CDCl₃) ppm:same as the spectrum of the compound of Reference Example 16. [α]_(D) :-1.5° (C=0.492,CHCl₃).

Reference Example 21

(S)-N-[3,5-Bis(trifluoromethyl)benzyl]-7,8-dihydro-7-(4-hydroxy-3-methylbutyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

(S)-4-Amino-2-methyl-1-butanol THP ether was used in place of(R)-4-amino-2-methyl-1-butanol THP ether in Reference Example 19 andreacted and treated in the same manner as in Reference Example 19, toobtain the entitled compound as colorless crystals. m.p. 213-215° C.(after once melted, this again solidified), 207-208° C. (re-melted)(recrystallized from ethyl acetate-isopropyl ether) NMR(200 MHz, CDCl₃)ppm: same as the spectrum of the compound of Reference Example 17.[α]_(D) : -2.7° (C=0.391,CHCl₃).

Reference Example 22

N-(2-Aminoethyl)-N-[3,5-bis(trifluoromethyl)benzyl]-2-chloro-4-phenyl-3-pyridinecarboxamide

Step 1

Thionyl chloride (0.15 ml) and DMF (catalytic amount) were added to aTHF (5 ml) solution of 2-chloro-4-phenyl-3-pyridinecarboxylic acid (145mg) and heated under reflux for 2 hours. The solvent was removed bydistillation, and the residue was dissolved in THF (5 ml). The resultingsolution was added to a mixture ofN-[3,5-bis(trifluoromethyl)benzyl]-N'-tert-butoxycarbonylethylenediamine(240 mg), triethylamine (0.26 ml) and THF (10 ml), while cooling withice, and stirred for 3 hours at room temperature. TheN-[3,5-bis(trifluoromethyl)benzyl]-N'-tert-butoxycarbonylethylenediamineused herein was prepared as an oily compound, by reactingethylenediamine with 3,5-bis(trifluoromethyl)benzyl methanesulfonate inTHF to give an oily compound ofN-[3,5-bis(trifluoromethyl)benzyl]ethylenediamine, followed by furtherreacting the compound with di-tert-butyl dicarbonate in the presence oftriethylamine in THF.

The solvent was removed from the reaction mixture, and water was addedto the residue, which was then extracted with ethyl acetate. The extractwas washed with water and dried, and the solvent was removed bydistillation. Thus, obtained wasN-[3,5-bis(trifluoromethyl)benzyl]-N-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-4-phenyl-3-pyridinecarboxamideas a pale yellow oil. NMR(200 MHz, CDCl₃) ppm: 1.20-1.60(total 9H,m),2.70-4.90(total 7H,m), 7.20-8.00(total 9H,m), 8.46(1H,d,J=5.2 Hz).

Step 2

A 4N-HCl/ethyl acetate solution (10 ml) was added to the compound asobtained in Step 1 and stirred for 30 minutes at room temperature. Thesolvent was removed by distillation, and aqueous sodiumhydrogencarbonate was added to the residue, which was then extractedwith ethyl acetate. The extract was washed with water and then dried,and the solvent was removed by distillation. Thus, the entitled compoundwas obtained as a pale yellow oil (349 mg). NMR(200 MHz, CDCl₃) ppm:2.30-3.70(4H,m), 4.15(1H×2/5,d,J=16.2 Hz), 4.38(1H×2/5,d,J=16.2 Hz),4.65(1H×3/5,d,J=15.2 Hz), 4.84(1H×3/5,d,J=15.2 Hz), 7.20-7.60(6H,m),7.65-7.80(6H,m), 8.47(1H,m).

Reference Example 23

N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-(3-hydroxypropyl)-4-phenyl-3-pyridinecarboxamide

Step 1

3-Amino-1-propanol was used in place of 2-aminoethanol in Step 1 inReference Example 12, reacted and treated in the same manner as in Step1 in Reference Example 12, to obtainN-[3,5-bis(trifluoromethyl)benzyl]-N-(3-hydroxypropyl)amine as colorlesscrystals. m.p. 57-58° C. (recrystallized from ethyl ether-hexane)NMR(200 MHz, CDCl₃) ppm: 1.77(2H,quintet,J=5.8 Hz), 2.89(2H,t,J=5.8 Hz),3.82(2H,t,J=5.8 Hz), 3.93(2H,s), 7.89(3H,s) Elemental Analysis for C₁₂H₁₃ NOF₆ : Calcd.(%): C, 47.85; H, 4.35; N, 4.65. Found (%): C, 47.76;H, 4.32; N, 4.65.

Step 2

The amine as obtained in Step 1 was used in place ofN-[3,5-bis(trifluoromethyl)benzyl]-N-(2-hydroxyethyl)amine in Step 2 inReference Example 12 reacted and treated in the same manner as in Step 2in Reference Example 12, to obtain the entitled compound as colorlesscrystals (the ratio of cis-trans isomers with respect to the amide bondwas about 3:1). m.p. 121-122° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 1.00-1.70(2H,m),2.75-3.20(2H,m), 3.35-3.55(3H,m), 4.06(1H×1/4,d,J=16.2 Hz),4.31(1H×1/4,d,J=16.2 Hz), 4.65(1H×3/4,d,J=15.2 Hz), 4.76(1H×3/4,d,J=15.2Hz), 7.20-7.55(6H,m), 7.72(2H,s), 7.80(1H,s), 8.47(1H,d,J=5.2 Hz)Elemental Analysis for C₂₄ H₁₉ N₂ O₂ F₆ Cl: Calcd.(%): C, 55.77; H,3.71; N, 5.42. Found (%): C, 55.65; H, 3.70; N, 5.57.

Reference Example 24

N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-(2-hydroxyethyl)-5-methyl-4-phenyl-3-pyridinecarboxamide

2-Chloro-5-methyl-4-phenyl-3-pyridinecarboxylic acid was used in placeof 2-chloro-4-phenyl-3-pyridinecarboxylic acid in Step 2 in ReferenceExample 12, reacted and treated in the same manner as in Step 2 inReference Example 12, to obtain the entitled compound as colorlesscrystals. m.p. 146-148° C. (recrystallized from ethyl acetate-isopropylether) NMR(200 MHz, CDCl₃) ppm: 2.09(3H,s), 3.02(1H,dt,J=15.0,5.6 Hz),3.25(1H,dt,J=15.0,5.6 Hz), 3.60(2H,m), 4.57(1H,d,J=15.2 Hz),4.79(1H,d,J=15.2 Hz), 7.05-7.50(5H,m), 7.62(2H,s), 7.76(1H,s),8.33(1H,s).

Reference Example 25

N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-(3-hydroxypropyl)-5-methyl-4-phenyl-3-pyridinecarboxamide

2-Chloro-5-methyl-4-phenyl-3-pyridinecarboxylic acid was used in placeof 2-chloro-4-phenyl-3-pyridinecarboxylic acid in Step 2 in ReferenceExample 12, reacted withN-[3,5-bis(trifluoromethyl)benzyl]-N-(3-hydroxypropyl)amine that hadbeen obtained in Step 1 in Reference Example 23, in place ofN-[3,5-bis(trifluoromethyl)benzyl]-N-(2-hydroxyethyl)amine, and treatedin the same manner as in Step 2 in Reference Example 12, to obtain theentitled compound as a pale yellow oil. NMR(200 MHz, CDCl₃) ppm:1.10-1.80(2H,m), 2.06(3H×1/2,s), 2.08(3H×1/2,s), 2.80-3.30(3H,m),3.35-3.70(1H,m), 4.08(1H×1/2,d,J=16.4 Hz), 4.39(1H×1/2,d,J=15.0 Hz),4.47(1H×1/2,d,J=16.4 Hz), 4.70(1H×1/2,d,J=15.0 Hz), 6.90-7.62(7H,m),7.72(1H×1/2,s), 7.77(1H×1/2,s), 8.28(1H×1/2,s), 8.31(1H×1/2,s).

Reference Example 26

(+/-)-N-[3,5-Bis(trifluoromethyl)benzyl]-7,8-dihydro-7-(2,3-dihydroxypropyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

The compound as obtained in Reference Example 3 was reacted with(+/-)-3-amino-1,2-propanediol and treated in the same manner as inReference Example 13, to obtain the entitled compound as a pale yellowfoam. NMR(200 MHz, CDCl₃) ppm: 2.20(3H,s), 3.50(2H,m), 4.02-4.30(5H,m),4.75(1H,b), 5.35(1H,b), 6.92-7.46(6H,m), 7.55(2H,s), 7.70(1H,s),8.63(1H,m), 8.83(1H,b).

Reference Example 27

N-Benzyl-8-oxo-5-phenyl-8H-pyrano[3,4-b]pyridine-6-carboxamide

The compound as obtained in Step 2 in Reference Example 9 was reactedwith benzylamine and treated in the same manner as in Reference Example3, to obtain the entitled compound as colorless crystals. m.p. 188-189°C. (recrystallized from acetone-ethyl ether) NMR(200 MHz, CDCl₃) ppm:4.48(2H,d,J=5.4 Hz), 7.2-7.4(8H,m), 7.49-7.65(5H,m),8.95(1H,dd,J=4.4,2.0 Hz)

Reference Example 28

N-(3,4-Dichlorobenzyl)-B-oxo-5-phenyl-8H-pyrano[3,4-b]pyridine-6-carboxamide

The compound as obtained in Step 2 in Reference Example 9 was reactedwith 3,4-dichlorobenzylamine and treated in the same manner as inReference Example 3, to obtain the entitled compound as colorlesscrystals. m.p. 198-200° C. (recrystallized from acetone-ethyl ether)NMR(200 MHz, CDCl₃) ppm: 4.44(2H,d,J=6.0 Hz), 7.10(1H,dd,J=8.2,2.0 Hz),7.25-7.70(10H,m), 8.96(1H,dd,J=4.3,1.7 Hz)

Reference Example 29

N-(3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-((S)-3-hydroxy-2-methylpropyl]-5-methyl-4-phenyl-3-pyridinecarboxamide

The same process as in Step 2 in Reference Example 12 was repeated,except that 2-chloro-5-methyl-4-phenyl-3-pyridinecarboxylic acid wasreacted withN-[3,5-bis(trifluoromethyl)benzyl]-N-[(S)-3-hydroxy-2-methylpropyl]amine[this was prepared by reacting 3,5-bis(trifluoromethyl)benzylmethanesulfonate with (S)-3-amino-2-methylpropanol in THF, and this is acolorless oily substance and was identified by NMR(200 MHz, CDCl₃) ppm:0.86(3H,d,J=6.8 Hz), 1.98(1H,m), 2.63(1H,dd,J=9.4,11.8 Hz),2.70-2.90(3H,m), 3.56(1H,dd,J=8.6,10.6 Hz), 3.71(1H,ddd,J=1.4,4.0,10.6Hz), 3.87(1H,d,J=13.8 Hz), 3.98(1H,d,J=13.8 Hz), 7.79(3H,s)] in place ofreacting 2-chloro-4-phenyl-3-pyridinecarboxylic acid withN-[3,5-bis(trifluoromethyl)benzyl]-N-(2-hydroxyethyl)amine, to obtainthe entitled compound as a colorless oily substance. NMR(200 MHz, CDCl₃)ppm: 0.60-0.82(3H,m), 1.50-2.00(1H,m), 2.00-2.15(3H,m), 2.15-3.92(4H,m),4.05-4.92(2H,m), 7.00-7.85(8H,m), 8.34(1H,m)

Reference Example 30

N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-[(R)-3-hydroxy-2-methylpropyl]-5-methyl-4-phenyl-3-pyridinecarboxamide

N-[3,5-Bis(trifluoromethyl)benzyl]-N-[(R)-3-hydroxy-2-methylpropyl]aminewas reacted and treated in the same manner as in Reference Example 29,in place ofN-[3,5-bis(trifluoromethyl)benzyl]-N-[(S)-3-hydroxy-2-methylpropyl]aminein Reference Example 29, to obtain the entitled compound as a colorlessoily substance. The NMR spectrum (200 MHz, CDCl₃) of the compoundobtained herein was the same as that of the compound obtained inReference Example 29.

Reference Example 31

N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-(2-hydroxyethyl)-6-methyl-4-phenyl-3-pyridinecarboxamide

Step 1

A mixture of ethyl 2-chloro-6-methyl-4-phenyl-3-pyridinecarboxylate(15.43 g), ethanol (70 ml) and aqueous 4N-sodium hydroxide solution (70ml) was heated under reflux for 2.5 hours. The reaction mixture wasconcentrated, and the resulting concentrate was made acidic (pH 3) byadding hydrochloric acid thereto and then extracted with ethyl acetate.The extract was washed with saturated aqueous sodium chloride solutionand dried, and the solvent was removed by distillation. Thus, obtainedwas 2-chloro-6-methyl-4-phenyl-3-pyridinecarboxylic acid as colorlesscrystals (11.2 g). m.p. 191-194° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 2.59(3H,s),7.16(1H,s), 7.45(5H,s), 9.53(1H,b)

Step 2

In place of 2-chloro-4-phenyl-3-pyridinecarboxylic acid in Step 2 inReference Example 12, 2-chloro-6-methyl-4-phenyl-3-pyridinecarboxylicacid (as obtained in the previous Step 1) was reacted and treated in thesame manner as in Step 2 in Reference Example 12, to obtain the entitledcompound as a pale-yellow, oily substance. NMR(200 MHz, CDCl₃) ppm:1.95-3.80(4H,m), 2.58(3H,s), 4.15(1H×2/5,d,J=16.2 Hz),4.41(1H×2/5,d,J=16.2 Hz), 4.75(1H×3/5,d,J=15.0 Hz), 4.85(1H×3/5,d,J=15.0Hz), 7.15(1H×3/5,s), 7.17(1H×2/5,d,J=15.0 Hz), 7.23-7.58(5H,m),7.74(2H,s), 7.78(1H,s)

Reference Example 32

N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-(3-hydroxypropyl)-6-methyl-4-phenyl-3-pyridinecarboxamide

The same process as in Step 2 in Reference Example 12 was repeated,except that 2-chloro-6-methyl-4-phenyl-3-pyridinecarboxylic acid wasreacted with N-[3,5-bis(trifluoromethyl)benzyl]-N-(3-hydroxypropyl)aminein place of reacting 2-chloro-4-phenyl-3-pyridinecarboxylic acid withN-[3,5-bis(trifluoromethyl)benzyl]-N-(2-hydroxyethyl)amine, to obtainthe entitled compound as a pale-yellow, oily substance. NMR(200 MHz,CDCl₃) ppm: 1.15-1.65(2H,m), 2.59(3H,s), 2.75-3.20(2H,m),4.06(1H×2/5,d,J=15.4 Hz), 4.31(1H×2/5,d,J=15.4 Hz), 4.65(1H×3/5,d,J=15.2Hz), 4.74(1H×3/5,d,J=15.2 Hz), 7.16(1H,s), 7.20-7.60(5H,m), 7.72(2H,s),7.78(1H,s)

Reference Example 33

N-[3,5-Bis(trifluoromethyl)benzyl]-N-(2-hydroxyethyl)-5-methyl-2-methylaminocarbonyl-4-phenyl-3-pyridinecarboxamide

Step 1

A mixture of diethyl 5-methyl-4-phenyl-2,3-pyridinedicarboxylate (13.0g) [this was prepared in accordance with the method described inJapanese Patent Laid-Open No. 62-106081, and this has a melting point of73-74° C. (after recrystallized from ethyl ether-isopropyl ether)],potassium hydroxide (20 g) and 70%-ethanol (200 ml) was heated underreflux for 3 hours. The solvent was removed by distillation, and theresidue was diluted with water and then washed with ethyl ether. The PHof the aqueous layer was adjusted to 2-3 by adding 2 N-hydrochloricacid, and then extracted with ethyl acetate. The extract was washed withsaturated saline solution and dried, and the solvent was removed bydistillation. Thus, obtained was5-methyl-4-phenyl-2,3-pyridinedicarboxylic acid as pale yellow crystals(3.06 g). m.p. 187-188° C. (recrystallized from THF-ethyl ether) NMR(200MHz, DMSO-d₆) ppm: 2.10(3H,s), 7.20-7.30(2H,m), 7.40-7.55(3H,m),8.65(1H,s)

Step 2

The compound (2.9 g) as obtained in the previous Step 1 was heated inacetic anhydride (50 ml) under reflux for 2 hours. The solvent wasremoved by distillation, and ethanol (50 ml) was added to the residueand stirred for 4 hours at room temperature. Then, the solvent wasremoved by distillation, and the residue was dissolved in ethyl acetate.The resulting solution was washed with saturated saline solution anddried, and the solvent was removed by distillation. Thus, obtained was amixture of 2-ethyl ester and 3-ethyl ester (about 3:2) of5-methyl-4-phenyl-2,3-pyridinedicarboxylic acid as a pale-brown, oilysubstance (3.39 g).

Step 3

DMF (3 drops) and oxalyl chloride (2.0 ml) were added to a THF (30 ml)solution of the oily substance (1.94 g) as obtained in Step 2, andstirred for 30 minutes at room temperature. The solvent was removed bydistillation, and the residue was dissolved in THF (40 ml).N-[3,5-Bis(trifluoromethyl)benzyl]-N-(2-hydroxyethyl)amine (2.2 g) andtriethylamine (2.0 ml) were added to the resulting solution and stirredfor 16 hours at room temperature. The reaction mixture was diluted withethyl acetate, then washed with water, diluted hydrochloric acid,aqueous potassium carbonate solution and saturated saline solution, anddried. The solvent was removed by distillation, and the residue waspurified by column chromatography (hexane:ethyl acetate=1:2) usingsilica gel to obtainN-[3,5-bis(trifluoromethyl)benzyl]-2-ethoxycarbonyl-N-(2-hydroxyethyl)-5-methyl-4-phenyl-3-pyridinecarboxamideas colorless crystals (1.31 g). m.p. 138-139° C. (recrystallized fromethyl acetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm:1.45(3H×1/4,t,J=7.1 Hz), 1.46(3H×3/4,t,J=7.1 Hz), 2.18(3H×3/4,s),2.19(3H×1/4,s), 2.82(1H,m), 3.2-3.7(3H,m). 4.15-4.62(4H,m),7.05-7.80(8H,m), 8.65(1H×3/4,s), 8.68(1H×1/4,s)

Step 4

40% Methylamine-methanol solution (15 ml) was added to a THF (5 ml)solution of the compound (377 mg) as obtained in Step 3 and stirred for16 hours at room temperature. The solvent was removed by distillation,and the entitled compound was obtained as a pale-yellow, oily substance(370 mg). NMR(200 MHz, CDCl₃) ppm: 2.12(3H×2/3,s), 2.14(3H×1/3,s),2.83(1H,m), 3.03(3H×1/3,d,J=5.2 Hz), 3.04(3H×2/3,d,J=4.8 Hz),3.25-3.80(3H,m), 4.30(1H×2/3,d,J=15 Hz), 4.36(1H×1/3,d,J=15 Hz),4.59(1H×1/3,d,J=15 Hz), 4.86(1H×2/3,d,J=15Hz), 7.0-7.9(8H,m),8.02(1H,2/3,bd), 8.17(1H×1/3,bd), 8.46(1H,s)

Reference Example 34

N-[3,5-Bis(trifluoromethyl)benzyl]-N-(2-hydroxyethyl)-2-methylaminocarbnyl-4-phenyl-3-pyridinecarboxamide

Step 1

In place of diethyl 5-methyl-4-phenyl-2,3-pyridinedicarboxylate in Step1 in Reference Example 33, diethyl 4-phenyl-2,3-pyridinedicarboxylate(see Japanese Patent Laid-Open No. 62-106081) was reacted and treated inthe same manner as in Step 1 in Reference Exaple 33, to obtain4-phenyl-2,3-pyridinedicarboxylic acid as pale yellow crystals. m.p.146-148° C. (recrystallized from THF-isopropyl ether) NMR(200 MHz, CDCl₃+DMSO-d₆) ppm: 7.3-7.6(6H,m), 8.69(1H,d,J=5.0 Hz)

Step 2

The compound as obtained in Step 1 was reacted and treated in the samemanner as in Step 2 in Reference Example 33, to obtain a mixture of2-ethyl ester and 3-ethyl ester (about 3:2) of4-phenyl-2,3-pyridinedicarboxylic acid as a pale-brown, oily substance.

Step 3

The oily substance as obtained in Step 2 was reacted and treated in thesame manner as in Step 3 in Reference Example 33, to obtainN-[3,5-bis(trifluoromethyl)benzyl]-2-ethoxycarbonyl-N-(2-hydroxyethyl)-4-phenyl-3-pyridinecarboxamideas a pale-yellow, oily substance. NMR(200 MHz, CDCl₃) ppm:1.48(3H,t,J=7.1 Hz.), 2.71(1H,m), 3.1-3.7(3H,m), 4.1-4.9(4H,m),7.18-7.52(6H,m), 7.65-7.82(3H,m), 8.78(1H×3.4,d,J=4.8 Hz),8.80(1H×1/4,d,J=4.8 Hz)

Step 4

The compound as obtained in Step 3 was reacted and 5 treated in the samemanner as in Step 4 in Reference Example 33, to obtain the entitledcompound as a pale-yellow, oily substance. NMR(200 MHz, CDCl₃) ppm:2.73(1H,m), 3.05(3H×1/3,d,J=5.0 Hz), 3.06(3H×2/3,d,J=5.0 Hz),3.1-3.9(3H,m), 4.29(1H×1/3,d,J=16 Hz), 4.52(1H×2/3,d,J=15 Hz),4.54(1H×1/3,d,J=16 Hz), 4.93(1H×2/3,d,J=15 Hz), 7.0-7.9(9H,m),7.95(1H×2/3,bd), 8.19(1H×1/3,bd), 8.59(1H,d,J=5.2 Hz)

Reference Example 35

N-Benzyl-2-ethoxycarbonyl-N-(2-hydroxyethyl)-5-methyl-4-phenyl-3-pyridinecarboxamide

The oily substance as obtained in Step 2 in Reference Example 33 wasreacted with N-benzyl-N-(2-hydroxyethyl)amine and treated in the samemanner as in Step 3 in Reference Example 33, to obtain the entitledcompound as a pale-yellow, oily substance. NMR(200 MHz, CDCl₃) ppm:1.44(3H×1/4,t,J=7.2 Hz), 1.46(3H×3/4,t,J=7.1 Hz), 2.15(3H×3/4,s),2.19(3H×1/4,s), 2.6-3.7(4H,m), 3.96(1H×3/4,d,J=15 Hz),4.00(1H×1/4,d,J=15 Hz), 4.4-4.6(2H+1H×1/4,m), 5.37(1H×3/4,d,J=15 Hz),6.48(2H×3/4,m), 6.82(2H×1/4,m), 7.0-7.6(8H,m), 8.65(1H×3.4,s),8.66(1H×1/4,s)

Reference Example 36

N-[3,5-Bis(trifluoromethyl)benzyl]-N-(3-hydroxypropyl)-5-methyl-2-methylaminocarbonyl-4-phenyl-3-pyridinecarboxamide

Step 1

The oily substance as obtained in Step 2 in Reference Example 33 wasreacted with N-[3,5-bis(trifluoromethyl)benzyl]-N-(3-hydroxypropyl)amineand treated in the same manner as in Step 3 in Reference Example 33 toobtainN-[3,5-bis(trifluoromethyl)benzyl]-2-ethoxycarbonyl-N-(3-hydroxypropyl)-5-methyl-4-phenyl-3-pyridinecarboxamideas a pale-yellow, oily substance. NMR(200 MHz, CDCl₃) ppm:1.44(3H×1/4,t,J=7.1 Hz), 1.45(3H×3/4,t,J=7.1 Hz), 1.60(2H,m),2.17(3H×3/4,s), 2.18(3H×1/4,s), 2.7-3.7(4H,m), 3.96(1H×1/4,d,J=16 Hz),4.35-4.60(3H+1H×3/4,m), 7.10-7.80(8H,m), 8.64(1H×3/4,s), 8.68(1H×1/4,s)

Step 2

The compound as obtained in Step 1 was reacted and treated in the samemanner as in Step 4 in Reference Example 33 to obtain the entitledcompound as a pale-yellow, oily substance. NMR(200 MHz, CDCl₃) ppm:1.3-1.9(2H,m), 2.11(3H×3/5,s), 2.14(3H×2/5,s), 2.7-3.8(4H,m),3.02(3H×3/5,d,J=5.2 Hz), 3.03(3H×2/5,d,J=5.2 Hz), 4.04(1H×2/5,d,J=16Hz), 4.28(1H×3/5,d,J=15 Hz), 4.46(1H×2/5,d,J=16 Hz), 4.82(1H×3/5,d,J=15Hz), 7.0-7.6(5H,m), 7.63(2H3/5,s), 7.67(2H×2/5,s), 7.73(1H,s),7.96(1H×3/5,bd), 8.06(1H×2/5,bd), 8.45(1H×3/5,s), 8.48(1H×2/5,s)

Reference Example 37

2-Chloro-N-(2-hydroxyethyl)-4-phenyl-N-(3,4,5-trimethoxybenzyl)-3-pyridinecarboxamide

NMR(200 MHz, CDCl₃) ppm: 2.05-2.50(2H,m), 2.80-4.00(12H,m),4.00-4.40(1H×3/2,m), 4.93(1H×1/2,d,J=14.2 Hz), 6.22(2H×1/2,s),6.55(2H×1/2,s), 7.25-7.70(6H,m), 8.42(1H×1/2,d,J=6.2 Hz),8.48(1H×1/2,d,J=5.8 Hz) (a 1:1 mixture of the amide rotamers).

Reference Example 38

2-Chloro-N-(3,4-dichlorobenzyl)-N-(2-hydroxyethyl)-4-phenyl-3-pyridinecarboxamide

NMR(200 MHz, CDCl₃) ppm: 1.80-3.85(5H,m), 3.96(1H×4/9,d,J=16.0 Hz),4.24(1H×4/9,d,J=16.0 Hz), 4.44(1H×5/9,d,J=15.2 Hz), 4.92(1H×5/9,d,J=15.2Hz), 6.50-6.85(2H,m), 7.10-7.70(7H,m), 8.46(1H,m) (a 5:4 mixture of theamide rotamers).

Reference Example 39

2-Chloro-N-(3,4-dimethoxybenzyl)-N-(2-hydroxyethyl)-4-phenyl-3-pyridinecarboxamide

NMR(200 MHz, CDCl₃) ppm: 2.70-4.30(12H,m), 4.53(1H×1/2,d,J=14.8 Hz),4.74(1H×1/2,d,J=14.8 Hz), 6.30-7.00(3H,m), 7.20-7.65(6H,m),8.39(1H×1/2,d,J=5.0 Hz), 8.46(1H×1/2,d,J=5.2 Hz) (a 1:1 mixture of theamide rotamers).

Reference Example 40

N-Benzyl-2-chloro-N-(2-hydroxyethyl)-4-phenyl-3-pyridinecarboxamide

NMR(200 MHz, CDCl₃) ppm: 2.27(1H×1/2,b), 2.60(1H×1/2,b),2.75-3.15(1H,m), 3.25-3.65(3H,m), 3.90(1H×1/2,d,J=15.4 Hz),4.26(1H×1/2,d,J=15.4 Hz), 4.49(1H×1/2,d,J=15.0 Hz), 4.95(1H×1/2,d,J=15.0Hz), 6.74(2H×1/2,m), 6.92(2H×1/2,m), 7.10-7.65(9H,m), 8.42(1H,m) (a 1:1mixture of the amide rotamers).

Reference Example 41

2-Chloro-N-(3-hydroxypropyl)-4-phenyl-N-(3,4,5-trimethoxybenzyl)-3-pyridinecarboxamide

NMR(200 MHz, CDCl₃) ppm: 1.10-2.30(3H,m), 2.70-4.30(14H+1H×3/7,m),4.88(1H×4/7,d,J=14.8 Hz), 6.18(2H×4/7,s), 6.52(2H×3/7,s),7.20-7.60(6H,m), 8.47(1H,m) (a 4:3 mixture of the amide rotamers).

Reference Example 42

N-Benzyl-2-chloro-N-[(S)-3-hydroxy-2-methylpropyl]-4-phenyl-3-pyridinecarboxamide

NMR(200 MHz, CDCl₃) ppm: 0.50-0.85(3H,m), 1.40-1.85(1H,m),2.20-3.75(5H,m), 3.80-5.15(2H,m), 6.60-7.65(11H,m), 8.42(1H,m) (a 2:1mixture of the amide rotamers).

Reference Example 43

N-Benzyl-2-chloro-N-[(R)-3-hydroxy-2-methylpropyl]-4-phenyl-3-pyridinecarboxamide

MR(200 MHz, CDCl₃) ppm: same as the spectrum of the compound ofReference Example 42.

Reference Example 44

N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-[(S)-3-hydroxy-2-methylpropyl]-4-phenyl-3-pyridinecarboxamide

NMR(200 MHz, CDCl₃) ppm: 0.53(3H×1/4,d,J=7.0 Hz), 0.63(3H×1/4,d,J=7.0Hz), 0.75(3H×1/4,d,J=6.8 Hz), 0.81(3H×1/4,d,J=6.8 Hz), 1.50-1.90(1H,m),2.42-3.80(5H,m), 4.00-4.95(2H,m), 7.10-7.90(9H,m), 8.42(1H,m) (a 1:1mixture of the amide rotamers).

Reference Example 45

N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-[(R)-3-hydroxy-2-methylpropyl]-4-phenyl-3-pyridinecarboxamide

NMR(200 MHz, CDCl₃) ppm: same as the spectrum of the compound ofReference Example 44.

Reference Example 46

N-Benzyl-7,8-dihydro-7-(4-hydroxybutyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

Step 1

Using the compound as obtained in Reference Example 2-Step 2 andbenzylamine, substantially the same reaction and work-up as ReferenceExample 2-Step 4 was conducted to giveN-benzyl-5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxamideas colorless crystals. m.p. 208-209° C. (recrystallized fromacetone-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 2.45(3H,s),4.48(2H,d,J=5.6 Hz), 7.10-7.40(10H,m), 7.58(2H,m), 8.94(1H,dd,J=3.6&2.2Hz).

Step 2

Using the compound as obtained in Step 1 and 4-amino-1-butanol,substantially the same reaction and work-up as Reference Example 13 wasconducted to give the entitled compound as colorless crystals. m.p.205-207° C. (recrystallized from acetone-isopropyl ether) NMR(200 MHz,CDCl₃) ppm: 1.48(2H,m), 1.83(2H,m), 2.45(3H,s), 2.86(1H,b),3.57(2H,t,J=5.9 Hz), 3.85(2H,m), 4.34(2H,d,J=6.0 Hz), 6.8-7.1(2H,m),7.10-7.35(8H,m), 7.50(1H,m), 7.55(1H,dd,J=8.4&1.4 Hz),8.60(1H,dd,J=4.0&1.4 Hz).

Reference Example 47

(R)-N-Benzyl-7,8-dihydro-7-(4-hydroxy-3-methylbutyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

Starting from the compound as obtained in Reference Example 46-Step 1and THP-ether of (R)-4-amino-2-methyl-1-butanol, substantially the samereaction and work-up as Reference Example 19 was conducted to give theentitled compound as colorless crystals. m.p. 226-227° C.(recrystallized from acetone-ethyl ether) NMR(200 MHz, CDCl₃) ppm:0.81(3H,d,J=6.6 Hz), 1.5-2.0(3H,m), 2.44(3H,s), 3.20-3.55(3H,m),3.93(2H,m), 4.31(2H,d,J=5.4 Hz), 6.75-6.90(2H,m), 7.1-7.3(8H,m),7.39(1H,dd,J=8.2&4.2 Hz), 7.61(1H,d,J=8.2 Hz), 8.68(1H,d,J=4.2 Hz).

Reference Example 48

(S)-N-Benzyl-7,8-dihydro-7-(4-hydroxy-3-methylbutyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

Starting from the compound as obtained in Reference Example 46-Step 1and THP-ether of (S)-4-amino-2-methyl-1-butanol, substantially the samereaction and work-up as Reference Example 19 was conducted to give theentitled compound as colorless crystals. m.p. 226-227° C.(recrystallized from acetone-ethyl ether) NMR(200 MHz, CDCl₃) ppm: sameas the spectrum of the compound of Reference Example 47.

Reference Example 49

(R)-7,8-Dihydro-7-(4-hydroxy-3-methylbutyl)-5-(4-methylphenyl)-8-oxo-N-(3,4,5-trimethoxybenzyl)-6-pyrido[3,4-b]pyridinecarboxamide

Step 1

Using the compound as obtained in Reference Example 2-Step 2 and3,4,5-trimethoxybenzylamine, substantially the same reaction and work-upas Reference Example 2-Step 4 was conducted to give5-(4-methylphenyl)-8-oxo-N-(3,4,5-trimethoxybenzyl)-8H-pyrano[3,4-b]pyridine-6-carboxamideas colorless crystals. m.p. 195-196° C. (recrystallized fromacetone-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 2.45(3H,s),3.84(3H,s), 3.85(6H,s), 4.40(2H,d,J=5.8 Hz), 6.50(2H,s), 7.17(2H,d,J=8.0Hz), 7.27(1H,b), 7.32(2H,d,J=8.0 Hz), 7.58(2H,m), 8.94(1H,dd,J=4.0&2.2Hz).

Step 2

Starting from the compound as obtained in Step 1 and THP-ether of(R)-4-amino-2-methyl-1-butanol, substantially the same reaction andwork-up as Reference Example 19 was conducted to give the entitledcompound as colorless crystals. m.p. 194-195° C. (recrystallized fromacetone-ethyl ether) NMR(200 MHz, CDCl₃) ppm: 0.84(3H,d,J=6.8Hz),1.5-2.0(3H,m), 2.38(3H,s), 3.2-3.6(3H,m), 3.65-3.95(2H,m), 3.80(6H,s),3.82(3H,s), 4.23(2H,d,J=6.0 Hz), 6.40(2H,s), 7.05-7.40(4H,m),7.32(1H,dd,J=8.2&4.2 Hz), 7.56(1H,dd,J=8.2&1.6 Hz), 7.80(1H,m),8.63(1H,dd,J=4.2&1.6 Hz).

Reference Example 50

(S)-7,8-Dihydro-7-(4-hydroxy-3-methylbutyl)-5-(4-methylphenyl)-8-oxo-N-(3,4,5-trimethoxybenzyl)-6-pyrido[3,4-b]pyridinecarboxamide

Starting from the compound as obtained in Reference Example 49-Step 1and THP-ether of (S)-4-amino-2-methyl-1-butanol, substantially the samereaction and work-up as Reference Example 19 was conducted to give theentitled compound as colorless crystals. m.p. 194-195° C.(recrystallized from acetone-ethyl ether) NMR(200 MHz, CDCl₃) ppm: sameas the spectrum of the compound of Reference Example 49.

Reference Example 51

(R)-N-(3,5-Dimethoxybenzyl)-7,8-Dihydro-7-(4-hydroxy-3-methylbutyl)-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxamide

Step 1

Using the compound as obtained in Reference Example 2-Step 2 and3,5-dimethoxybenzylamine, substantially the same reaction and work-up asReference Example 2-Step 4 was conducted to giveN-(3,5-dimethoxybenzyl)-5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxamideas colorless crystals. m.p. 154-155° C. (recrystallized from ethylacetate-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 2.45(3H,s),3.78(6H,s), 4.41(2H,d,J=5.4 Hz), 6.41(3H,m), 7.17(2H,d,J=8.0 Hz),7.23(1H,b), 7.33(2H,d,J=8.0 Hz), 7.58(2H,m), 8.94(1H,dd,J=4.0&2.2 Hz).

Step 2

Starting from the compound as obtained in Step 1 and THP-ether of(R)-4-amino-2-methyl-1-butanol, substantially the same reaction andwork-up as Reference Example 19 was conducted to give the entitledcompound as colorless crystals. m.p. 169-172° C. (recrystallized fromacetone-isopropyl ether) NMR(200 MHz, CDCl₃) ppm: 0.85(3H,d,J=6.8 Hz),1.62(1H,m), 1.79(2H,m), 2.40(3H,s), 3.11(1H,b), 3.25-3.60(2H,m),3.76(6H,s), 3.86(2H,m), 4.23(2H,d,J=5.6 Hz), 6.25(2H,d,J=2.2 Hz),6.35(1H,t,J=2.2 Hz), 7.15-7.35(4H,m), 7.30(1H,dd,J=8.4&4.2 Hz),7.44(1H,m), 7.56(1H,dd,J=8.4&1.6 Hz), 8.65(1H,dd,J=4.2&1.6 Hz).

The compounds as described in Reference Example 52-55 were obtained aspale yellow oily substances using2-chloro-4-(4-methylphenyl)-3-pyridinecarboxylic acid [prepared from2-cyano-3-methyl-3-(4-methylphenyl)propenoic acid ethyl ester bycondensation with N,N-dimethylacetamide dimethyl acetal, followed bycyclization using hydrogen chloride and alkaline hydrolysis of the estergroup: m.p. 205-208° C. (decomposed)] andN-substituted-N-(substituted)benzylamines{i.e.,N-benzyl-N-(2-hydroxyethyl)amine,N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-hydroxyethyl)amine,N-benzyl-N-[(S)-3-hydroxy-2-methylpropyl]amine, andN-[3,5-bis(trifluoromethyl)benzyl]3-N-[(S)-3-hydroxy-2-methylpropyl]amine,respectively} by substantially the same reaction and work-up asReference Example 12-Step 2. The physico-chemical data are describedbelow.

Reference Example 52

N-Benzyl-2-chloro-N-(2-hydroxyethyl)-4-(4-methylphenyl)-3-pyridinecarboxamide

NMR(200 MHz, CDCl₃) ppm: 2.43(3H×1/2,s), 2.46(3H×1/2,s), 2.70-3.80(total4H,m), 3.90(1H×1/2,d,J=15.4 Hz), 4.24(1H×1/2,d,J=15.4 Hz),4.51(1H×1/2,d,J=15.2 Hz), 4.94(1H×1/2,d,J=15.2 Hz), 6.74(1H,m),6.97(1H,m), 7.10-7.55(8H,m), 8.40(1H,m) (a 1:1 mixture of the amiderotamers).

Reference Example 53

N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-(2-hydroxyethyl)-4-(4-methylphenyl)-3-pyridinecarboxamideNMR(200 MHz, CDCl₃) ppm: 2.36(3H×7/11,s), 2.44(3H×4/11,s),2.80-3.80(total 4H,m), 4.16(1H×4/11,d,J=16.2 Hz),4.41(1H×4/11,d,J=16.2Hz), 4.77(1H×7/11,d,J=15.0 Hz),4.90(1H×7/11,d,J=15.0 Hz), 7.10-7.50(6H,m), 7.76(2H,m), 8.42(1H,m) (a7:4 mixture of the amide rotamers).

Reference Example 54

N-Benzyl-2-chloro-N-[(S)-3-hydroxy-2-methylpropyl]4-(4-methylphenyl)3-pyridinecarboxamide

NMR(200 MHz, CDCl₃) ppm: 0.59(3H×1/4,d,J=7.0 Hz), 0.66(3H×1/4,d,J=7.0Hz), 0.77(3H×1/4,d,J=3.8 Hz), 0.80(3H×1/4,d,J=3.8 Hz), 1.40-1.90(1H,m),2.30-2.50(3H,m), 2.50-3.80(total 5H,m), 3.80-4.42(2H×3/4,m),5.05(2H×1/4,m), 6.60-7.50(total 10H,m), 8.40(1H,m) (a 1:1 mixture of theamide rotamers).

Reference Example 55

N-[3,5-Bis(trifluoromethyl)benzyl]2-chloro-N-[(S)-3-hydroxy-2-methylpropyl]4-(4-methylphenyl)-3-pyridinecarboxamide

NMR(200 MHz, CDCl₃) ppm: 0.54(3H×1/4,d,J=7.0 Hz), 0.63(3H×1/4,d,J=7.0Hz), 0.79(3H×1/4,d,J=7.0 Hz), 0.84(3H×1/4,d,J=7.0 Hz), 1.50-1.90(1H,m),2.25-2.45(3H,m), 2.45-3.90(total 5H,m), 4.05-4.45(1H,m),4.50-4.95(1H,m), 7.00-7.20(1H,m), 7.20-7.50(total 5H,m),7.70-7.85(2H,m), 8.42(1H,m) (a 1:1 mixture of the amide rotasmers).

Formulation Example 1

    ______________________________________                                        (1) Compound of Example 2                                                                          10.0 mg                                                  (2) Lactose          60.0 mg                                                  (3) Corn starch      35.0 mg                                                  (4) Hydroxypropylmethyl cellulose                                                                   3.0 mg                                                  (5) Magnesium stearate                                                                              2.0 mg                                                  ______________________________________                                    

A mixture of 10.0 mg of the compound as obtained in Example 2, 60.0 mgof lactose and 35.0 mg of corn starch was granulated along with 0.03 mlof an aqueous solution of 10 wt. % hydroxypropylmethyl cellulose(containing 3.0 mg of hydroxypropylmethyl cellulose), then dried at 40°C. and sieved. The granules thus obtained were mixed with 2.0 mg ofmagnesium stearate and tabletted. The green tablet thus obtained wassugar-coated with an aqueous suspension comprising sucrose, titaniumdioxide, talc and arabic gum. The thus-coated tablet was glazed withbees wax to obtain a finally-coated tablet.

Formulation Example 2

    ______________________________________                                        (1) Compound of Example 1                                                                         10.0 mg                                                   (2) Lactose         70.0 mg                                                   (3) Corn starch     50.0 mg                                                   (4) Soluble starch   7.0 mg                                                   (5) Magnesium stearate                                                                             3.0 mg                                                   ______________________________________                                    

10.0 mg of the compound as obtained in Example 2

and 3.0 mg of magnesium stearate were granulated along with 0.07 ml ofan aqueous solution of soluble starch (containing 7.0 mg of solublestarch), then dried and mixed with 70.0 mg of lactose and 50.0 mg ofcorn starch. The mixture was tabletted into a tablet.

Radioligand Receptor Binding Inhibitory Activity

Binding Inhibitory Activity Using Receptor from Human Lymphoblast Cells(IM-9)

The method of M. A. Cascieri et al. "Molecular Pharmacology 42, p.458(1992)" was modified and used. The receptor was prepared from humanlymphoblast cells (IM-9). IM-9 cells (2×10⁵ cells/ml) were inoculatedand incubated for 3 days (one liter), which was then subjected tocentrifuge for 5 minutes at 500×g to obtain cell pellets. The pelletswere washed once with phosphate buffer (Flow Laboratories, CAT. No.28-103-05), which were then crushed using Polytron.homogenizer"Kinematika, Germany" in 30 ml of 50 mM Tris-HCl buffer (pH 7.4)containing 120 mM sodium chloride, 5mM potassium chloride, 2 μg/mlchymostatin, 40 μg/ml bacitracin, 5 μg/ml phosphoramidon, 0.5 mMphenylmethyl sulfonyl fluoride, 1 mM ethylenediamine tetra-acetic acid,which was subjected to centrifuge at 40,000×g for 20 minutes. Theresidue was washed twice with 30 ml of the above-mentioned buffer, whichwas then preserved frozen (-80° C.) as a specimen of the receptor.

The specimen was suspended in a reaction buffer (50 mM Tri-HCl buffer(pH 7.4), 0.02% bovine serum albumin, 1 mM phenylmethylsulfonylfluoride, 2 μg/chymostatin, 40 μg/ml bacitracin, 3 mM manganesechloride) and 100 ul portion was the suspension was used in thereaction. After addition of the sample and ¹²⁵ I-BHSP (0.46 KBq), thereaction was allowed to proceed in 0.2 ml of reaction buffer at 25° C.for 30 minutes. The amount of nonspecific binding was determined byadding substance P at a final concentration of 2×10⁻⁶ M. After thereaction, using a cell harvester (290 PHD, Cambridge Technology, Inc,U.S.A.), rapid filtration was carried out through a glass filter (GF/B,Whatman, U.S.A.) to stop the reaction. After washing three times with250 ul of 50 mM of Tris-HCl buffer (pH 7.4) containing 0.02% bovineserum albumin, the radioactivity remaining on the filter was determinedwith a gamma counter. Before use, the filter was immersed in 0.1%polyethyleneimine for 24 hours and air-dried. The antagonistic activityof each test drug, in terms of the concentration necessary to cause 50%inhibition (IC₅₀) under the above-described conditions, was expressed innM [Table 1]. (Radioligand means substance P labelled with ¹²⁵ I.) Fromthe test results, it is understood that the compounds (I) and (Ia) orsalts thereof of the present invention have an excellent substance Preceptor antagonistic effect.

                  TABLE 1                                                         ______________________________________                                        Test Compound                                                                 (Example No.)   IC.sub.50 (nM)                                                ______________________________________                                        2               0.28                                                          3               0.76                                                          8               1.2                                                           10              0.66                                                          13              0.17                                                          14              0.28                                                          15              0.88                                                          16              0.17                                                          17              0.23                                                          18              0.43                                                          23              1.1                                                           24              1.6                                                           25              0.1                                                           31              0.36                                                          35              0.44                                                          37              0.28                                                          38              0.74                                                          39              0.42                                                          40              0.17                                                          45              0.12                                                          47              0.2                                                           ______________________________________                                    

Binding Inhibitory Activity Toward Human NK₂ Receptor

First strand cDNA synthesized by reverse transcription at 48 C° for 1 hfrom 2 μg of human stomach poly A⁺ RNA (Clontech Laboratories, Inc.,USA) with Superscript RNase H⁻ reverse transcriptase (GIBCO BRL LifeTechnologies, Inc., USA) and a gene specific 3'-primer(5'CTAACCCCTACCTCCCAACACTGCC-ACATTGGG-3') which was designed accordingto the published nucleotide sequence coding for human NK₂ receptorreported by A. Graham, B. Hopkins, S. J. Powell, P. Danks, and I. Briggs[Biochemical and Biophysical Research Communications 177, pp8-16(1991)]. Polymerase chain reaction (PCR) was performed at 95° C. for1 min, 55° C. for 2 min, 72° C. for 3 min for 50 cycles using tag DNApolymerase (Takara Shuzoh, Shiga, Japan), the above mentioned 3'-primerand a gene specific 5'-primer (5'-GAGCCAGGTCCTTTGTTCCAGACCCAGAAGCAG-3')which was also designed according to the published nucleotide sequenceof human NK₂ receptor cCNA reported by A. Graham et al. described above.The resultant PCR product, 1.3 kilobase-pair DNA fragment was clonedinto the Hincll site of pBluescript II SK⁺ (Stratagene, USA).

The identity of the obtained clone was confirmed by nucleotide sequenceanalysis. In order to obtain an expression vector, the 1.3 kilobase-pairDNA fragment of human NK₂ receptor cDNA was placed downstream of the SRαpromoter [Y. Takebe, M. Seiki, J. Fujisawa, P. Hoy, K. Yokota, K. Arai,M. Yoshida, and N. Arai "Molecular and Cellular Biology 8, p466-472(1988)"].

COS-7 cells were cultured in DMEM medium (ICN Biomedicals, Inc., USA)supplemented with 10% fetal bovine serum at density of 3×10⁶ per 175-cm²flask (Nunc, Denmark) for 1 day. The cells were transfected with 30 μgof the above mentioned expression vector and 150 μg of transfectam(BioSepra, Inc., USA) at 37° C. for 5 h. After 3 days, cells were washedwith phosphate buffer (ICN Biomedicals, Inc., Cat. No. 2810305, USA)containing 0.1% ethylenediamine tetra-acetic acid, detached from a flaskand centrifuged at 170×g for 5 min to obtain cell pellets. The cellpellets were suspended in 50 mM Tris-HCl buffer (pH 7.4) (containing 120mM sodium chloride, 5 mM potssium chloride, 2 μg/ml chymostatin, 40μg/ml bacitracin, 5 μg/ml phosphoramidon, 0.5 mM phenylmethylsulfonylfluoride and 1 mM ethylenediamine tetra-acetic acid), and were thendisrupted by a Physicotron handy micro homogenizer NS-310E (Nichi-on-iRikakiki Seisakusho, Chiba, Japan), which was subjected to centrifuge at40,000×g for 60 min. The resulting pellet was washed twice with theabove mentioned buffer, which was then preserved frozen at -80° C. as aspecimen of the receptor.

The specimen was suspended in reaction buffer (50 mM Tris-HCl buffer (pH7.4) containing 0.02% bovine serum albumin, 1 mM phenylmethylsulfonylfluoride, 2 μg/ml chymostatin, 40 μg/ml bacitracin and 3 mM manganesechloride) to give a protein concentration of 0.6 mg/ml, and 0.1 ml ofthe portion of the suspension was employed in the reaction. Afteraddition of a test compound and (2-[¹²⁵ l]iodohistidyl¹)Neurokinin A(Amersham, UK) (74 TBq/mmol, 1.48 kBq, final concentration of 0.1 nM) toa final volume of 0.2 ml, the mixture was incubated at room temperaturefor 60 min in a 96-well plate. Then the mixture was filtered through aglass fiber filter (UniFilter-96, GF/B, Packard Instrument, Inc., USA)under reduced pressure on a Filter Mate Cell Harvester (PackardInstrument, Inc., USA). After washing the filter three times with 0.3 mlof the above mentioned reaction buffer, the radioactivity remaining onthe filter was determined on a TopCound Micro Scintillation Counter(Packard Instrument, Inc., USA). The nonspecific binding was defined asthe binding activity in the presence of 10×10⁻⁶ M of neurokinin A(Peptide Instituted, Osaka, Japan). The filters were presoaked overnightin 0.5% bovine serum albumin. The antagonistic activity of each testcompound was expressed in nM in terms of the concentration necessary tocause 50% inhibition (IC₅₀) under the above described conditions [Table2].

                  TABLE 2                                                         ______________________________________                                        Test Compound                                                                 (Example No.)   IC.sub.50 (nM)                                                ______________________________________                                        22              7.5                                                           27              6.2                                                           33              9.5                                                           ______________________________________                                    

From Table 2, it is apparent that the compound (I) or salts thereof ofthe present invention have excellent inhibitory activity toward humanNK₂ receptor.

Inhibitory Effect on Plasma Extravasation Induced by Capsaicin inTrachea of Guinea Pigs

Guinea pigs (Hartley type white male guinea pige), (n=6) wereanesthetized with 35 mg/kg of pentobarbital injected intraperitoneally(i.p.), then test compounds were administered intravenously (i.v.).After 5 minutes, a mixed solution of capsaicin (150 μg/kg) and Evans'blue dye (20 mg/kg) was administered intravenously to cause reaction.Ten minutes later, test animals were sacrificed by cutting the aorta,then perfused through pulmonary artery with 50 ml of physiologicalsaline. The trachea was excised, and its wet weight was measure. Thetrachea was incubated at room temperature in 1 ml of acetone-0.3% sodiumsulfate (7:3) overnight and Evans' blue dye was extracted from thetrachea. The extract solution was centrifuged at 2800 rpm for 5 minutes.The amount of Evans' blue dye in the supernatant was quantified bymeasuring absorbance at 620 mm.

Plasma extravasation was expressed in terms of the amount of Evans' bluedye (μg) relative to the weight of the trachea (g). The efficacy of thedrug was evaluated by calculating the % inhibition in accordance withthe following formula, or expressed in terms of ##EQU1## A: the amountof Evan's blue dye (μg/g) in each test animal B: The mean amount ofEvan's blue dye (μg/g) of the group untreated with capsaicin.

C: the mean amount of Evan's blue dye (μg/g) of control group

the dose (μg/kg) necessary to cause 50% inhibition (ID ₅₀) under theabove-described conditions [Table 3].

                  TABLE 3                                                         ______________________________________                                                        Dose (i.v)                                                                             Inhibition.sup.a)                                    Test Compound   μg/kg %                                                    (Example No.)   (or ID.sub.50 ; μg/kg, i.v).sup.b)                         ______________________________________                                        2               (7.2)                                                         3               (4.2)                                                         6               (11)                                                          7               (2.6)                                                         8               (3.2)                                                         12              (41)                                                          13              (1.6)                                                         14              (3.2)                                                         15              10       68.4***                                              16              10       60.5***                                              17              (1.9)                                                         18              (2.6)                                                         22              100      41.2*                                                23              100      64.0*                                                24              100      53.1*                                                ______________________________________                                         .sup.a) Dunnett's test: *p < 0.05, **p < 0.01, ***p < 0.001                   .sup.b) ID.sub.50 values are given in parentheses.                       

From Table 3, it is apparent that the compound (I) or salts thereof ofthe present invention have excellent inhibitory action on the plasmaextravasation induced by capsaicin.

What is claimed is:
 1. A compound of the formula: ##STR53## wherein ringM is a heterocyclic ring wherein --X. . . . . Y<is --N═C<;and n is aninteger from 1 to 6, or a salt thereof; R^(a) and R^(b) are the same ordifferent and represent, independently, (1) a hydrogen atom, (2) a C₁₋₆alkyl group optionally having from 1 to 5 substituents selected from(a)a hydroxyl group, (b) a C₁₋₆ alkoxy group, (c) a C₁₋₆ alkylthio group,(d) an amino group, (e) a C₁₋₇ acylamino group, (f) a carboxyl group,(g) a nitro group, (h) a mono- or di-C₁₋₆ alkylamino group, (i) a mono-or di-C₁₋₆ cycloalkylamino group, (j) a C₆₋₁₀ arylamino group, (k) a5-membered to 9-membered cyclicamino group which may have 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to thenitrogen atom in the amino group, (l) a 5-membered to 6-memberedaromatic heterocyclic group having from 1 to 3 hetero atoms selectedfrom nitrogen, oxygen and sulfur atoms, in addition to carbon atoms, (m)a 5-membered to 9-membered non-aromatic heterocyclic ring having from 1to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, inaddition to carbon atoms, (n) a C₁₋₄ alkylsulfonylamino group, (o) aC₁₋₆ alkyl-carbonyloxy group and (p) a halogen atom, (3) an optionallyhalogenated C₁₋₆ alkoxy group, (4) an optionally halogenated C₁₋₆alkylthio group, (5) a C₃₋₁₀ cycloalkyl group, (6) a C₆₋₁₀ aryl group,(7) a C₁₋₇ acylamino group, (8) a C₁₋₃ acyloxy group, (9) a hydroxygroup, (10) a nitro group, (11) a cyano group, (12) an amino group, (13)a mono- or di-C₁₋₆ alkylamino group, (14) a 5-membered to 9-memberedcyclicamino group which may have 1 to 3 hetero atoms selected fromnitrogen, oxygen and sulfur atoms, in addition to the nitrogen atom inthe amino group, (15) a C₁₋₆ alkylcarbonylamino group, (16) a C₁₋₆alkylsulfonylamino group, (17) a C₁₋₆ alkoxycarbonyl group, (18) acarboxyl group, (19) a C₁₋₆ alkylcarbonyl group, (20) a carbamoyl group,(21) a mono- or di-C₁₋₆ alkylcarbamoyl group, (22) C₁₋₆ alkylsulfonylgroup; the Ring B is a benzene ring which may have 1 to 4 substituentsselected from (1) a halogen atom, (2) a C₁₋₆ alkyl group optionallyhaving from 1 to 5 substituents selected from(a) a hydroxyl group, (b)an amino group, (c) a carboxyl group, (d) a nitro group, (e) a mono- ordi-C₁₋₆ alkylamino group, (f) a C₁₋₆ alkyl-carbonyloxy group and (g) ahalogen atom, (3) an optionally halogenated C₁₋₆ alkoxy group, (4) anoptionally halogenated C₁₋₆ alkylthio group, (5) a C₆₋₁₀ aryl group, (6)a C₁₋₇ acylamino group, (7) a C₁₋₃ acyloxy group, (8) a hydroxy group,(9) a nitro group, (10) a cyano group, (11) an amino group, (12) a mono-or di-C₁₋₆ alkylamino group, (13) a 5-membered to 9-membered cyclicaminogroup which may have 1 to 3 hetero atoms selected from nitrogen, oxygenand sulfur atoms, in addition to the nitrogen atom in the amino group,(14) a C₁₋₆ alkylcarbonylamino group, (15) a C₁₋₆ alkylsulfonylaminogroup, (16) a C₁₋₆ alkoxycarbonyl group, (17) a carboxyl group, (18) aC₁₋₆ alkylcarbonyl group, (19) a carbamoyl group, (20) a mono- ordi-C₁₋₆ alkylcarbamoyl group, (21) a C₁₋₆ alkylsulfonyl group; the RingC is a benzene ring optionally having 1 to 5 substituents selected from(1) a halogen atom, (2) an optionally halogenated C₁₋₁₀ alkyl group, (3)an amino-substituted C₁₋₄ alkyl group, (4) a mono- or di-C₁₋₄alkylamino-substituted C₁₋₄ alkyl group, (5) a carboxyl-substituted C₁₋₄alkyl group, (6) a hydroxy-substituted C₁₋₄ alkyl group, (7) a C₁₋₄alkoxy-carbonyl-substituted C₁₋₄ alkyl group, (8) a C₃₋₁₀ cycloalkylgroup, (9) a nitro group, (10) a cyano group, (11) a hydroxyl group,(12) an optionally-halogenated C₁₋₁₀ alkoxy group, (13) anoptionally-halogenated C₁₋₄ alkylthio group, (14) an amino group, (15) amono- or di-C₁₋₄ alkylamino group, (16) a 5-membered to 9-memberedcyclic amino group optionally having 1 to 3 hetero atoms selected fromnitrogen, oxygen and sulfur atoms, in addition to the nitrogen atom inthe amino group, (17) a C₁₋₄ alkyl-carbonylamino group, (18) anaminocarbonyloxy group, (19) a mono- or di-C₁₋₄ alkylaminocarbonyloxygroup, (20) a C₁₋₄ alkylsulfonylamino group, (21) a C₁₋₄ alkoxy-carbonylgroup, (22) an aralkyloxycarbonyl group, (23) a carboxyl group, (24) aC₁₋₆ alkyl-carbonyl group, (25) a C₃₋₆ cycloalkyl-carbonyl group, (26) acarbamoyl group, (27) a mono- or di-C₁₋₄ alkylcarbamoyl group, (28) aC₁₋₆ alkylsulfonyl group and (29) a 5-membered or 6-membered aromaticmonocyclic heterocyclic group having 1 to 4 hetero atoms selected fromnitrogen, oxygen and sulfur atoms, which may have 1 to 3 substituentsselected from an optionally halogenated C₁₋₄ alkyl; the Ring Z is##STR54## wherein p is an integer of from 2 to 5 and Z₂ is a hydrogenatom, an C₁₋₄ alkyl group or a hydroxyl group.
 2. A compound as claimedin claim 1, wherein n is
 1. 3. A compound as claimed in claim 1, whereinR^(a) and R^(b) are the same or different and represent,independently,(1) a hydrogen atom, (2) a C₁₋₆ alkoxy-C₁₋₆ alkyl group,(3) a C₁₋₆ alkylthio-C₁₋₆ alkyl group, (4) an amino-C₁₋₆ alkyl group,(5) a C₁₋₇ acylamino-C₁₋₆ alkyl group, (6) a mono- or di-C₁₋₆alkylamino-C₁₋₄ alkyl group, (7) C₃₋₁₀ cycloamino-C₁₋₆ alkyl group, (8)a C₁₋₆ alkyl group having 5-membered or 6-membered cycloamino optionallysubstituted by C₁₋₆ alkyl group, (9) a C₁₋₆ alkylsulfonylamino-C₁₋₆alkyl group, or (10) a C₁₋₆ alkylcarbonyloxy-C₁₋₆ alkyl Ring B is abenzene ring optionally having 1 to 3 substituents selected from ahalogen atom, an optionally halogenated C₁₋₄ alkyl group and anoptionally halogenated C₁₋₄ alkoxy group; Ring C is a benzene ringopitionally having 1 to 3 substituents selected from a halogen atom, anoptionally halogenated C₁₋₄ alkyl group, an optionally halogenated C₁₋₄alkoxy group, an amino group optionally substituted by C₁₋₄ alkyl group,a C₁₋₃ acyloxy group and a hydroxyl group; and n is an integer of
 1. 4.A process for producing a compound as claimed in claim 1, characterizedby cyclizing a compound of a formula: ##STR55## wherein D is--O(CH₂)_(p) -- wherein p has the same meaning as that in claim 1, E is##STR56## L represents a leaving group, and the other symbols are thesame meanings as those in claim 1, or a salt thereof.
 5. Apharmaceutical composition comprising a compound or pharmaceuticallyacceptable salt thereof as claimed in claim
 1. 6. A method ofantagonizing Substance P receptor to a subject in need comprising thestep of:administering a composition of claim 1 to said subject in apharmaceutically effective amount.
 7. A method of antagonizingneurokinin A receptor to a subject in need comprising the stepof:administering a composition of claim 1 to said subject in apharmaceutically effective amount.
 8. A method for antagonizingtachykinin receptor in mammals which comprises administrating to asubject in need, an effective amount of a compound or pharmaceuticallyacceptable salt thereof as claimed in claim
 1. 9. A method for treatingdisorders of micturition in mammals which comprises administrating-to asubject in need an effective amount of a compound or pharmaceuticallyacceptable salt thereof as claimed in claim
 1. 10. A method for treatingdisorders of asthma, migraine, irritable bowel syndrome, pain, cough oremesis in mammals which comprises administrating to a subject in need aneffective amount of a compound or pharmaceutically acceptable saltthereof as claimed in claim
 1. 11. A compound as claimed in claim 1,which may be any oneof:4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;5-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine;4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-7-methyl-5-oxo-6-phenylpyrido[3,2-f][1,5]oxazepine;5-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-methyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,4]oxazocine;(S)-5-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-3,8-dimethyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine;(R)-5-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-3,8-dimethyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine;4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-methyl-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;5-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-9-methyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine;8-Acetoxymethyl-4-[3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;9-Acetoxymethyl-5-[3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine;4-[3,5-bis(trifluoromethyl)benzyl]-8-chloromethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-methoxymethyl-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-(2-methylethyl)-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-methylthiomethyl-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;8-Aminomethyl-4-[3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-methylaminomethyl-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;4-[3,5-Bis(trifluoromethyl)benzyl]-8-dimethylaminomethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;4-[3,5-Bis(trifluoromethyl)benzyl]-8-cyclopropylaminomethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-(N-methylpiperazinomethyl)-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;8-Acetylaminomethyl-4-[3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-methanesulfonylaminomethyl-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;4-[3,5-Bis(trifluoromethyl)benzyl]-8-hydroxymethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine-8-carboxylicacid;4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine-8-carboxamide;4-[3,5-Bis(trifluoromethyl)benzyl]-N-methyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine-8-carboxamide;4-[3,5-Bis(trifluoromethyl)benzyl]-N,N-dimethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine-8-carboxamide;4-[3,5-Bis(trifluoromethyl)benzyl]-N-n-butyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine-8-carboxamide;4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenyl-8-piperidinocarbonylpyrido[3,2-f][1,4]oxazepine;4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-morpholinocarbonyl-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;4-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-8-[1-(4-methylpiperazinyl)carbonyl]-5-oxo-6-phenyl-pyrido[3,2-f][1,4]oxazepine-8-carboxamide;2,3,4,5-Tetrahydro-5-oxo-6-phenyl-4-(3,4,5-trimethoxybenzyl)pyrido[3,2-f][1,4]oxazepine;4-(3,4-Dichlorobenzyl)-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;4-(3,4-Dimethoxybenzyl)-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;4 -Benzyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine;2,3,4,5-Tetrahydro-6-oxo-7-phenyl-5-(3,4,5-trimethoxybenzyl)-6H-pyrido[2,3-b][1,5]oxazocine;(S)-5-Benzyl-2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine;(R)-5-Benzyl-2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine;(S)-5-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine;(R)-5-[3,5-Bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H-pyrido[2,3-b][1,5]oxazocine;4-Benzyl-2,3,4,5-tetrahydro-5-oxo-6-(4-methylphenyl)pyrido[3,2-f][1,4]oxazepine;4-[3,5-Bis(trifluoromethyl)benzyl]2,3,4,5-tetrahydro-5-oxo-6-(4-methylphenyl)pyrido[3,2-f][1,4]oxazepine;(S)-5-Benzyl-2,3,4,5-tetrahydro-3-methyl-7-(4-methylphenyl)-6-oxo-6H-pyrido[2,3-b][1,5]oxazocine;and(S)-5-[3,5-Bis(trifluoromethyl)benzyl]2,3,4,5-tetrahydro-3-methyl-7-(4-methylphenyl)-6-oxo-6H-pyrido[2,3-b][1,5]oxazocine.